Spiro and dispiro 1,2,4-trioxolane antimalarials

ABSTRACT

A means and method for treating malaria, schistosomiasis, and cancer using a spiro or dispiro 1,2,4-trioxolane is described. The preferred 1,2,4-trioxolanes include a spiroadamantane group on one side of the trioxolane group, and a spirocyclohexyl on the other side of the trioxolane group, whereby the spirocyclohexyl ring is preferably substituted at the 4-position. In comparison to artemisinin semisynthetic derivatives, the compounds of this invention are structurally simple, easy to synthesize, non-toxic, and potent against malarial parasites.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This invention is a continuation-in-part of co-pending patentapplication number PCT/US02/19767 filed Jun. 21, 2002, which claimspriority to U.S. Pat. No. 6,486,199, the disclosures of which are herebyexpressly incorporated by reference.

FIELD OF THE INVENTION

[0002] This invention relates to compositions and methods for treatingmalaria.

[0003] Specifically, this invention relates to pharmaceuticalcompositions including spiro and dispiro trioxolanes, and methods oftheir use and manufacture.

BACKGROUND OF THE INVENTION

[0004] Malaria is an acute and often chronic infectious diseaseresulting from the presence of protozoan parasites within red bloodcells. Caused by single-celled parasites of the genus Plasmodium,malaria is transmitted from person to person by the bite of femalemosquitos.

[0005] Although once prevalent in North America and other temperateregions of the world, today malaria occurs mostly in tropical andsubtropic countries. Each year, between 400 million and 600 millionpeople contract the disease, and 1.5 million to 2.7 million die of thedisease.

[0006] Four species of Plasmodium protozoan parasites are generallyresponsible for malaria, including Plasmodium vivax, Plasmodiumfalciparum, Plasmodium malariae, and Plasmodium ovale. Of the four,Plasmodium falciparum is the most dangerous, accounting for half of allclinical cases of malaria and 90% of deaths from the disease.

[0007] The transmission of malaria begins when a female mosquito bites ahuman already infected with the malaria parasite. When the infectedmosquito bites another human, sporozoites in the mosquito's saliva aretransferred into the blood, which then travel to the liver. In theliver, the sporozoites divide rapidly, then enter the bloodstream wherethey invade red blood cells. Inside these blood cells, the merozoitesmultiply rapidly until they cause the red blood cells to burst,releasing into the blood stream a new generation of merozoites that theninfect other red blood cells.

[0008] The symptoms associated with malaria are generally associatedwith the bursting of the red blood cells. The destruction of the redblood cells spills wastes, toxin, and other debris into the blood. Thisin turn causes an intense fever that can leave the infected individualexhausted and bedridden. More severe symptoms associated with repeatinfections and/or infection by Plasmodium falciparum include anemia,severe headaches, convulsions, delirium and, in some instances, death.

[0009] The treatment of malaria has been especially difficult due to theability of malaria parasites to develop resistance to drugs. Quinine, anantimalarial compound that is extracted from the bark of the SouthAmerican cinchona tree, is one of the oldest and most effectivepharmaceuticals in existence. The downside to quinine is that it isshort-acting, and fails to prevent disease relapses. Further, quinine isassociated with side effects ranging from dizziness to deafness.

[0010] Chloroquine is a synthetic chemical similar to quinine. It becamethe drug of choice for malaria when it was developed in the 1940s due toits effectiveness, ease of manufacture, and general lack of sideeffects. However, in the last few decades, malaria parasites in manyareas of the world have become resistant to chloroquine.

[0011] Mefloquine is another synthetic analog of quinine that has beenused in the treatment of malaria. Malaria parasites have also developedresistance to mefloquine, however. Mefloquine is also associated withundesirable central nervous side effects in some patients, includinghallucinations and vivid nightmares.

[0012] Antifolate drugs are effective against malaria parasites byinhibiting their reproduction. Although the parasites have alsodeveloped a resistance to antifolate drugs, the drugs can still be usedeffectively in combination with other types of antimalarials. The use ofcombination therapies in treating malaria has the drawbacks of beinginconvenient and expensive, however.

[0013] More recent developments in the treatment of malaria haveinvolved the use of the peroxide functional group, as exemplified by thedrug artemisinin, which contains a unique 1,2,4-trioxane heterocyclicpharmacophore. The antimalarial action of artemisinin is due to itsreaction with the iron in free heme molecules in the malaria parasitewith the generation of free radicals leading to cellular destruction.

[0014] The discovery of artemisinin (qinghaosu), a naturally occurringendoperoxide sesquiterpene lactone (Meshnick et al., 1996; Vroman et al.1999; Dhingra et al., 2000) initiated a substantial effort to elucidateits molecular mechanism of action (Jefford, 1997; Cumming et al., 1997)and to identify novel antimalarial peroxides (Dong and Vennerstrom,2001). Many synthetic 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and otherendoperoxides have been prepared.

[0015] Although the clinically useful semisynthetic artemisininderivatives are rapid acting and potent antimalarial drugs, they haveseveral disadvantages including recrudescence, neurotoxicity, (Wesche etal., 1994) and metabolic instability. (White, 1994). A fair number ofthese compounds are quite active in vitro, but most suffer from low oralactivity. (White, 1994; van Agtmael et al., 1999). Although manysynthetic antimalarial 1,2,4-trioxanes have since been prepared (Cumminget al., 1996; Jefford, 1997), there exists a need in the art to identifynew peroxide antimalarial agents, especially those which are easilysynthesized, are devoid of neurotoxicity, and which possess improvedpharmacokinetic properties, e.g. improved stability, oral absorption,etc.

[0016] Accordingly, it is a primary objective of the present inventionto provide compositions and methods for prophylaxis and treatment ofmalaria using spiro and dispiro 1,2,4-trioxolanes.

[0017] It is a further objective of the present invention to provide acomposition and method for prophylaxis and treatment of malaria usingspiro and dispiro 1,2,4-trioxolanes that is nontoxic.

[0018] It is a further objective of the present invention to provide acomposition and method for prophylaxis and treatment of malaria usingspiro and dispiro 1,2,4-trioxolanes that is metabolically stable andorally active.

[0019] It is yet a further objective of the present invention to providea composition and method for prophylaxis and cost-effective treatment ofmalaria using spiro and dispiro 1,2,4-trioxolanes that do not involve atreatment regimen of more than three days.

[0020] It is a further objective of the present invention to providecompositions and methods for prophylaxis and treatment of malaria usingspiro and dispiro 1,2,4-trioxolanes that can be used either asstand-alone medicaments or in combination with other agents.

[0021] It is still a further objective of the present invention toprovide novel intermediates for synthesizing compositions forprophylaxis and treatment of malaria.

[0022] The method and means of accomplishing each of the aboveobjectives as well as others will become apparent from the detaileddescription of the invention which follows hereafter.

SUMMARY OF THE INVENTION

[0023] The invention describes a method and composition for treatingmalaria with spiro and dispiro 1,2,4-trioxolanes, their prodrugs andanalogues. The trioxolanes of this invention are sterically hindered onone side of the trioxolane heterocycle in order to provide chemical andmetabolic stability to the trioxolane ring for better in vivo activity.In one embodiment, the spiro and dispiro trioxolanes are stericallyhindered with an unsubstituted, mono-, di-, or poly-substituted C₅-C₁₂spiro cycloalkyl group, which may be spiroadamantane. In thisembodiment, the spiro and dispiro trioxolanes may include aspirocyclohexyl that is functionalized or substituted at the 4-positionor a spiropiperidyl ring that is functionalized or substituted at thenitrogen atom. In another embodiment, the trioxolanes of this inventioninclude an alkyl bridge from the 4-position of the spirocyclohexyl ringconnecting a substituent that is most preferably a weak base. Theinvention embraces achiral, achiral diastereomers, racemic mixtures, aswell as enantiomeric forms of the compounds.

[0024] The trioxolanes of this invention possess excellent potency andefficacy against Plasmodium parasites, and a low degree ofneurotoxicity. In addition, several of the trioxolanes are suitable forboth oral and non-oral administration. Moreover, in comparison toartemisinin semisynthetic derivatives, the compounds of this inventionare structurally simple, easy and inexpensive to synthesize, and can beused effectively alone or in conjunction with other antimalarials.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0025] The present invention relates to the development of spiro anddispiro 1,2,4-trioxolanes for use in the prophylaxis and treatment ofmalaria. The present invention is predicated upon the unexpecteddiscovery that trioxolanes that are relatively sterically hindered on atleast one side of the trioxolane heterocycle provide metabolic andchemical stability to the trioxolane ring, thereby providing better invivo activity, especially with respect to oral administration.

[0026] As used herein the term “prophylaxis-effective amount” refers toa concentration of compound of this invention that is effective ininhibiting or preventing infection and subsequent disease by malarialparasites. Likewise, the term “treatment-effective amount” refers to aconcentration of compound that is effective in treating malaria in termsof preventing an increase in the concentration of malarial parasites,decreasing the concentration of malarial parasites, and/or “curing” amalaria infection, i.e. survival for. 30 days post-infection.

[0027] Tetrasubstituted trioxolanes are relatively stable peroxidiccompounds based on literature precedent (Griesbaum et al., 1997a;1997b). This may be due, in part, to the lack of α-hydrogen atoms. Thepresent inventors have synthesized new compounds in the trioxolane classhaving both superior antimalarial potency and oral efficacy.Furthermore, the compounds of this invention have low toxicity, andhalf-lives conducive to treatment of malaria which are believed willpermit short-term treatment regimens comparing favorably to otherartemisinin-like drugs. These compounds may also be used in malariaprophylaxis.

[0028] In previous application, the-present inventors disclosed certainnovel tetrasubstituted trioxolanes having the following structuralformula:

[0029] wherein R₁, R₂, R₃, and R₄ represent combinations of ringsystems, acyclic systems, and functional groups that provide sufficientsteric hindrance about the trioxolane ring in order to give the ringchemical and metabolic stability. R₁, R₂, R₃ and R₄ may be the same ordifferent, and may be a linear or branched alkyl, aryl, or alkaryl groupwhich is optionally substituted. In the alternative, R₁ and R₂ takentogether and/or R₃ and R₄ taken together may form an alicyclic groupwhich is optionally interrupted by one or more oxygen, sulfur ornitrogen atoms and which group is optionally substituted. In no eventmay any of R₁, R₂, R₃ or R₄ be hydrogen.

[0030] In one embodiment, the compounds include those whereby R₁ and R₂taken together and/or R₃ and R₄ taken together is a mono- ordi-substituted C₅-C₁₂ spirocycloalkyl group which is optionallyinterrupted by one or more oxygen, sulfur, or nitrogen atoms, and whichgroup is optionally substituted. In another embodiment, R₁ and R₂ takentogether or R₃ and R₄ is spiroadamantane.

[0031] The present invention discloses a new embodiment of trioxolanecompounds having the following structure:

[0032] The spirocyclohexyl ring may be optionally interrupted by one ormore oxygen, sulfur or nitrogen atoms. In this regard, R₁ and R₂ may bethe same or different, and may be hydrogen, substituted or unsubstitutedlinear or branched alkyl, aryl, and alkaryl groups and substituted orunsubstituted alicyclic groups that may be interrupted by one or moreoxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromaticor heterocyclic groups that may be interrupted by one or more oxygen,sulfur or nitrogen atoms, a hydroxy group, or a halogen. In oneembodiment, R₁ or R₂ is an amide. It has been unexpectedly found thatamide-containing substituents at the 4-position provide antimalarialcompounds with good oral absorption, good antimalarial activity, andgood pharmacokinetics, i.e. rates of absorption, metabolism, andelimination that are suitable and advantageous for the prophylaxis andtreatment of malaria.

[0033] In another embodiment, the compounds of this invention have thefollowing structural formula:

[0034] whereby R₃ is (CH₂)_(n)—Y. In this formula, Y represents afunctional group that, in one embodiment, is non-acidic, and in anotherembodiment is a weak base. The Y functional group may be an alkyl,ketone, acid, alcohol, amine, amide, sulfonamide, guanidine, ether,ester, oxime, urea, oxime ether, sulfone, lactone, carbamate,semicarbazone, phenyl, or heterocycle. In one embodiment, n=1. The alkyl“bridge” group has been found to improve the metabolically stability(i.e. oral activity and pharmacokinetics) of the antimalarial compoundsof this invention.

[0035] In another embodiment of the invention, the trioxolanes are weakbases, which provide an ideal combination of high intrinsic potency andgood oral activity. Two promising trioxolane structural subtypes areweak base amides of trioxolane amine OZ209 and trioxolane acid OZ78.These compounds have one of the following two structural formulas:

[0036] Other substituents at the 4-position of the spirocyclohexyl ringare also possible that fall within the scope of this invention. Thespirocyclohexyl ring may also be substituted at other positions besidesthe 4-position. For instance, the inventors have synthesized severalcompounds substituted at the 2-position of the spirocyclohexyl ring thatprovide excellent antimalarial potency.

[0037] In another embodiment of this invention, the compounds include analkyl group connecting the substituent at the 4-position to thespirocyclohexyl ring. In one embodiment, the alkyl group is methyl orethyl. In another embodiment, the alkyl group is methyl. The substituentmay also be directly attached to the 4-position of the spirocyclohexylring.

[0038] The present inventors have identified two orally active leaddispiro-1,2,4-trioxolanes, OZ03 and OZ05:

[0039] These trioxolanes have IC₅₀s between 1 and 5 ng/ml against P.falciparum in vitro, and presumably possess good therapeutic indices asno toxicity is evidence for either compound in a neuroblastoma cell lineor at single 640 mg/kg doses in mice in the Rane test. These resultscontrast with published data (de Almeida Barbosa et al., 1992; 1996)disclosing the weak in vitro antimalarial potency of several tricyclictrioxolanes, the best of which has an IC₅₀ of 2000 ng/ml against P.falciparum in vitro.

[0040] A notable feature of these trioxolanes in comparison to theartemisinin semisynthetic derivatives is their structural simplicity. Apotential advantage of trioxolanes over both trioxanes (Jefford, 1997;Cumming et al., 1997) and tetraoxanes (Vennerstrom et al., 2000) is amore convenient access to structurally diverse, non-symmetrical, and inmany cases, achiral compounds.

[0041] Below are several dispiro 1,2,4-trioxolanes synthesized inaccordance with the teachings of this invention. “OZ” is an internaldesignation for these compounds that will be used throughout theremainder of the application for convenience. The structures ofOZ01-OZ90 have been previously disclosed in prior application U.S. Ser.No. 09/886,666 (U.S. Pat. No. 6,486,199), and are therefore not repeatedhere.

OZ Series 11 (OZ91-OZ99)

[0042]

OZ Series 12 (OZ100-OZ108)

[0043]

OZ Series 13 (OZ109-OZ117)

[0044]

OZ Series 14 (OZ118-OZ126)

[0045]

OZ Series 15 (OZ127-OZ135)

[0046]

OZ Series 16 (OZ136-OZ144)

[0047]

OZ Series 17 (OZ145-OZ153)

[0048]

OZ Series 18 (OZ154-OZ162)

[0049]

OZ Series 19 (OZ163-OZ171)

[0050]

OZ Series 20 (OZ172-OZ180)

[0051]

OZ Series 21 (OZ181-OZ189)

[0052]

OZ Series 22 (OZ190-OZ198)

[0053]

OZ Series 23 (OZ199-OZ207)

[0054]

OZ Series 24 (OZ208-OZ216)

[0055]

OZ Series 25 (OZ217-OZ225)

[0056]

OZ Series 26 (OZ226-OZ234)

[0057]

OZ Series 27 (OZ235-OZ243)

[0058]

OZ Series 28 (OZ244-OZ252)

[0059]

OZ Series 29 (OZ253-OZ261)

[0060]

OZ Series 30 (OZ262-OZ270)

[0061]

OZ Series 31 (OZ271-OZ279)

[0062]

OZ Series 32 (OZ280-OZ288)

[0063]

OZ Series 33 (OZ289-OZ297)

[0064]

OZ Series 34 (OZ298-OZ306)

[0065]

OZ Series 35 (OZ307-OZ315)

[0066]

OZ Series 36 (OZ316-OZ324)

[0067]

OZ Series 37 (OZ325-OZ333)

[0068]

OZ Series 38 (OZ334-OZ342)

[0069]

[0070] The prototype trioxolanes of this invention are OZ03 and OZ05.Preferred compounds identified thus far include OZ03, OZ05, OZ11, OZ25,OZ27, OZ61, OZ71, OZ78, OZ127, OZ145, OZ156, OZ163, OZ175, OZ177, OZ179,OZ181, OZ189, OZ205, OZ207, OZ209, OZ210, OZ219, OZ227, OZ229, OZ235,OZ255, OZ256, OZ257, OZ263, OZ264, OZ265, OZ266, OZ267, OZ268, OZ269,OZ270, OZ271, OZ277, OZ281, OZ279, OZ288, OZ289, OZ290, OZ296, OZ297,OZ298, OZ301, OZ305, OZ309, OZ315, OZ317, OZ319, OZ320, OZ323, OZ329,OZ333, OZ335, OZ336, OZ337, OZ338, and OZ339. The most preferredcompounds are OZ78, OZ163, OZ181, OZ207, OZ209, OZ255, OZ256, OZ257,OZ263, OZ264, OZ267, OZ271, OZ277, OZ279, OZ301, OZ305, OZ315, OZ317,OZ319, OZ323, OZ329, OZ338, and OZ339, with OZ277 and OZ279 being thebest of those compounds identified thusfar. In general, the highest invitro potency against malarial parasites is obtained for trioxolanesfunctionalized or substituted at the 4-position of the spirocyclohexylring. As a general rule, non-symmetrical, achiral trioxolanes are alsopreferred.

[0071] Notable features of these spiro and dispiro 1,2,4-trioxolanes incomparison to the artemisinin seminsynthetic derivatives are theirstructural simplicity and ease of synthesis.

[0072] For example, dispiro trioxolanes may be easily synthesized by thecoozonolysis of the O-methyl oximes of cycloalkanones in the presence ofthe requisite cycloalkanone derivatives according to the method ofGriesbaum et al. (1997a; 1997b) as illustrated below for the symmetricaldispiro cyclohexyl trioxolane:

[0073] If yields are low in this coozonolysis reaction, yields canimprove dramatically when the O-methyloxime and ketone are “reversed.”This novel procedure provides a uniquely convenient method to synthesizespiro and dispiro trioxolanes. The trioxolanes may be purified bycrystallization or by flash column chromatography. Their structures andpurity may be confirmed by analytical HPLC, ¹H and ¹³C NMR, IR, meltingpoint and elemental analysis.

[0074] Recently, Griesbaum et al. (1997b) discovered thattetrasubstituted 1,2,4-trioxolanes are conveniently obtained byozonolysis of O-alkyl ketone oximes in the presence of carbonylcompounds. Advantages of the oxime ether route over the alkene approachinclude convenient synthesis of starting materials (oxime ethers vs.tetrasubstituted alkenes), higher yield and selectivity of formation ofdesired trioxolanes by the judicious selection of paired reactionsubstrates.

[0075] Formation of a trioxolane from an oxime ether and a ketone ispresumed to be a three-step process. The sequence begins by theelectrophilic addition of ozone to the oxime double bond to form aprimary ozonide. Second, the very unstable primary adduct fragments to areactive carbonyl oxide driven in part by the concomitant expulsion ofthe relatively stable methyl nitrite. Third, the carbonyl oxideundergoes a [3+2] cycloaddition with a ketone to give the secondaryozonide or 1,2,4-trioxolane. It remains to be

[0076] determined whether this is a stepwise or a concertedrecombination process.

[0077] As illustrated above by the synthesis of OZ03, all of the newtarget dispiro trioxolanes contain a spiroadamantane and can besynthesized by the coozonolysis of adamantanone O-methyl oxime in thepresence of the requisite cycloalkanone derivative. The preferredreaction solvents for the coozonolysis reactions are hydrocarbonsolvents such as pentane or cyclohexane; more polar solvents tend todecrease the yield of the reaction. When ketones are not readily solublein pentane or cyclohexane, a mixed solvent (pentane/methylene chloride)or methylene chloride alone may be used. Several factors govern theratio of oxime ether to ketone. In some reactions, in order to avoiddiperoxide (1,2,4,5-tetraoxane) formation, to preclude diozonideformation from diketones, and to promote the reaction with readilypentane soluble ketones, excess ketone (2:1) is used. Most commonly inthe discovery synthesis stage, and especially in cases where ketones arenot readily soluble in pentane, expensive, or difficult to remove in thereaction workup, a 1:1 ratio of ketone to oxime ether may be used. Inlarge scale trioxolane syntheses, a 1.5-fold excess of oxime ether canbe used to achieve higher conversions of ketones into the desiredproduct trioxolanes without causing purification problems.

[0078] There are several examples of where post-ozonolysistransformations were used to obtain trioxolane target compoundsdifficult, or in some cases, impossible to obtain directly (Kashima etal., 1987) by the coozonolysis method. Trioxolane tertiary alcohols OZ90and

[0079] OZ108 can be obtained by methyllithium treatment of trioxolaneketone OZ05 and trioxolane ester OZ70, respectively. In other reactions,trioxolane lactone OZ17 and trioxolane alcohol OZ32 were obtained bytreatment of OZ05 with m-CPBA and sodium borohydride, respectively. Inaddition, various oxime ethers, hydrazones, ketals, and amines(reductive amination with sodium triacetoxyborohydride) were alsoobtained from trioxolane ketone OZ05 in good to excellent yields. In theexamples noted above, it is evident that troxolane ketone OZ05 is a keyintermediate as its ketone functional group provides a convenient meansfor functional group transformation.

[0080] Further evidence of the stability of these trioxolanes toreducing agents is shown by the reduction of trioxolane esters OZ70 andOZ61 into their corresponding trioxolane alcohols OZ119 and OZ89 with amixture of lithium borohydride and lithium triethylborohydride, and thehydrazinolysis of the trioxolane phthalimides OZ136 and

[0081] OZ146 into their corresponding trioxolane amines OZ137 and OZ209.

[0082] As shown in the examples below, trioxolane esters can beconveniently converted into their corresponding trioxolane acids.

[0083] In addition to trioxolane ketone OZ05, trioxolane amine mesylateOZ209, trioxolane ester OZ61 and trioxolane acid OZ78, trioxolanealcohols OZ1 19 and OZ89 have and will continue to be key intermediatesfor post-ozonolysis synthetic transformations. A recent example is the

[0084] synthesis of trioxolane triazole OZ177 in a reaction between themesylate derivative of OZ119 and the sodium salt of 1,2,4-triazole.

[0085] It has been found that the coozonolysis method using oxime methylethers offers a rapid, flexible, and predictable access to structurallydiverse trioxolanes. In fact, several key trioxolanes that have servedas important building blocks have been prepared in large scale includingOZ05 (100 mmol), OZ61 (100 mmol), and OZ146 (60 mmol), with no decreasein reaction yields over the usual 5-10 mmol scale. Furthermore, bothOZ61 and OZ146 can be conveniently isolated as white solids by additionof ethanol to the crude reaction mixtures.

[0086] Differential scanning calorimetry (DSC) experiments (Cammenga,and Epple, 1995) reveal that these compounds have good thermalstability, comparable to artemisinin. The average Tm, dec was 160±15° C.compared to a Tm, dec of 181° C. for artemisinin. It is presumed thatthermal decomposition of these trioxolanes was initiated by formation ofa 1,5 diradical produced by homolytic cleavage of the peroxide bond ofthe trioxolane ring.

[0087] Since most of the target trioxolanes contain the symmetricalspiroadamantane structural framework, their stereochemistry is largely afunction of the starting material ketone structure or reagents used inpost-ozonolysis reactions. For OZ27 and other similarly 1,4-substitutedtrioxolanes, two achiral diastereomers are possible. However, asexemplified by OZ27, the majority of these trioxolanes were isolated assingle achiral diastereomers rather than as mixtures of two achiraldiastereomers. For example, in OZ27, no chirality is present since thetrioxolane ring and phenyl substituent are in a 1,4 relationship in asix membered ring. Such compounds possess a plane of symmetry.

[0088] As determined by X-ray crystallography, the assignment ofstereochemistry for OZ78, OZ209 and their derivatives was determined tobe cis where the peroxide oxygens are in an axial position.

[0089] The starting material 2-adamantanone may be obtained from AldrichChemical Co. or from TCI American Organic Chemicals or may also besynthesized. Persons skilled in the art can readily ascertain otherappropriate means of synthesizing the starting materials and compoundsin accordance with this invention.

[0090] The spiro and dispiro trioxolane compositions of the presentinvention may be generally used for the prophylaxis and treatment ofmalaria. The trioxolane compositions of the present invention areadministered along with a pharmaceutically acceptable carrier. Anypharmaceutically acceptable carrier may be generally used for thispurpose, provided that the carrier does not significantly interfere withthe stability or bioavailability of the trioxolane compounds of thisinvention.

[0091] The trioxolanes of this invention can be administered in anyeffectively pharmaceutically acceptable form to warm blooded animals,including human and other animal subjects, e.g. in topical, lavage,oral, suppository, parenteral, or infusible dosage forms, as a topical,buccal, sublingual, or nasal spray or in any other manner effective todeliver the agents. The route of administration will preferably bedesigned to optimize delivery and/or localization of the agents totarget cells.

[0092] In addition to the active compounds i.e. the trioxolanes, thepharmaceutical compositions of this invention may contain suitableexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Oraldosage forms encompass tablets, capsules, and granules. Preparationswhich can be administered rectally include suppositories. Other dosageforms include suitable solutions for administration parenterally ororally, and compositions which can be administered buccally orsublingually.

[0093] The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself well known in the art. Forexample the pharmaceutical preparations may be made by means ofconventional mixing, granulating, dragee-making, dissolving,lyophilizing processes. The processes to be used will depend ultimatelyon the physical properties of the active ingredient used.

[0094] Suitable excipients are, in particular, fillers such as sugarsfor example, lactose or sucrose mannitol or sorbitol, cellulosepreparations and/or calcium phosphates, for example, tricalciumphosphate or calcium hydrogen phosphate, as well as binders such asstarch, paste, using, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents may be added,such as the above-mentioned starches as well as carboxymethyl starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as sodium alginate. Auxiliaries are flow-regulating agentsand lubricants, for example, such as silica, talc, stearic acid or saltsthereof, such as magnesium stearate or calcium stearate and/orpolyethylene glycol. Oral dosage forms may be provided with suitablecoatings which, if desired, may be resistant to gastric juices.

[0095] For this purpose concentrated sugar solutions may be used, whichmay optionally contain gum arabic, talc, polyvinylpyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate, dyestuffs and pigments may beadded to the tablet coatings, for example, for identification or inorder to characterize different combination of compound doses.

[0096] Other pharmaceutical preparations which can be used orallyinclude push-fit capsules made of gelatin, as well as soft, sealedcapsules made of gelatin and a plasticizer such as glycerol or sorbitol.The push-fit capsules can contain the active compounds in the form ofgranules which may be mixed with fillers such as lactose, binders suchas starches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, liquid paraffin, or liquid polyethylene glycols. In additionstabilizers may be added. Possible pharmaceutical preparations which canbe used rectally include, for example, suppositories, which consist of acombination of the active compounds with the suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,paraffin hydrocarbons, polyethylene glycols, or higher alkanols. Inaddition, it is also possible to use gelatin rectal capsules whichconsist of a combination of the active compounds with a base. Possiblebase material include for example liquid triglycerides, polyethyleneglycols, or paraffin hydrocarbons.

[0097] Suitable formulations for parenteral administration includeaqueous solutions of active compounds in water-soluble orwater-dispersible form. In addition, suspensions of the active compoundsas appropriate oily injection suspensions may be administered. Suitablelipophilic solvents or vehicles include fatty oils for example, sesameoil, or synthetic fatty acid esters, for example, ethyl oleate ortriglycerides. Aqueous injection suspensions may contain substanceswhich increase the viscosity of the suspension, including for example,sodium carboxymethyl cellulose, sorbitol and/or dextran. Suchcompositions may also comprise adjuvants such as preserving, wetting,emulsifying, and dispensing agents. They may also be sterilized, forexample, by filtration through a bacteria-retaining filter, or byincorporating sterilizing agents into the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved or suspended in sterile water, saline, or other injectablemedium prior to administration.

[0098] In addition to administration with conventional carriers, activeingredients may be administered by a variety of specialized deliverydrug techniques which are known to those of skill in the art, such asportable infusion pumps.

[0099] The trioxolane compositions of the present invention areadministered along with a pharmaceutically acceptable carrier in anamount sufficient to prevent malarial infection and/or treat an activeinfection. The trioxolane compounds of this invention have extremely lowtoxicity and a low degree of side effects even at high doses. The dosingrange of the trioxolane compositions will vary depending on a number offactors, such as whether it is used for prophylaxis or treatment of anactive infection, route of administration, dosing schedule, etc. Ingeneral, the therapeutic dose of trioxolane may range between about0.1-1000 mg/kg/day, with between about 1-100 mg/kg/day being preferred.The foregoing doses may be administered as a single dose or may bedivided into multiple doses for administration. The trioxolanecompositions may be administered once to several times daily. Formalaria prevention, a typical dosing schedule could be, for example,2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposuretaken up until 1-2 weeks post-exposure.

[0100] The spiro and dispiro trioxolanes of this invention have beenfound to be effective in the treatment of schistosomiasis.Schistosomiasis ranks second behind malaria in terms of socioeconomicand public health importance in tropical and subtropical areas. Thedisease is endemic in 74 developing countries, infecting more than 200million people in rural agricultural and peri-urban areas. An estimated500-600 million people worldwide are at risk from the disease.

[0101] The major forms of human schistosomiasis are caused by fivespecies of water-borne flatworm, or blood flukes, called schistosomes.One of these species is Schistosoma mansoni, which has been reported in53 countries in Africa, the Eastern Mediterranean, the Caribbean, andSouth America. The parasites enter the body through contact withinfested surface water, primarily among people engaged in agricultureand fishing. The parasites normally infect the host during the cercaria,or larval stage. Once inside the host, the cercaria develop into adultsor schistosomes.

[0102] Current treatments for schistosomiasis have focused primarily onprophylaxis, i.e. prevention of host infection by cercaria. Currently,praziquantel is the most widely used drug for treatment ofschistosomiasis. While artemether has demonstrated activity in theprophylaxis of schistosomiasis, it has not shown any activity againstadult S. mansoni.

[0103] It has now been unexpectedly discovered that the spiro anddispiro trioxolanes of this invention are active against both cercariaand adult S. mansoni, S. japonicum when administered in the dosages andmanner outlined above with respect to treatment of malarial parasites.It is also believed the trioxolanes of this invention will be activeagainst S. haematobium. Preferred compounds identified for use in thetreatment of schistosomiasis include OZ05, OZ11, OZ23, OZ25, OZ28, OZ32,OZ71, OZ78, OZ89, OZ90, OZ119, OZ145, OZ179, OZ205, OZ207, and OZ209.Most preferred compounds are OZ78, OZ207, and OZ209. Preferred dosinglevels of the spiro and dispiro trioxolanes are about 100-200 mg/kg/dayorally. The prototype trioxolanes of this invention are OZ03 and OZ05.

[0104] The spiro and dispiro trioxolanes of this invention may also haveeffectiveness in the treatment of cancer. Compounds having anendoperoxide moiety that is reactive with heme and iron have shown anability to kill cancer cells. (See e.g. U.S. Pat. No. 5,578,637, thedisclosure of which is hereby incorporated by reference). As noted withrespect to artemisinin, trioxolanes' mechanism of action againstmalarial parasites is based on the ability of trioxolane compounds toreact with the iron in free heme molecules in malaria parasites, withthe generation of free radicals leading to cellular destruction.Similarly, trioxolanes are selective against cancer cells due to thehigher concentration of transferrin receptors on cancer cell membranesthat pick up iron at a higher rate than normal cells. In the presence ofthe trioxolanes of this invention, the cancer cells will accumulate highconcentrations of free radicals, leading to cell death. For cancertreatment, the trioxolanes of this invention may be administered in thedoses and manner outlined above.

[0105] Other drugs besides trioxolanes which are compatible with thecarrier ingredients may also be incorporated into the carrier. Suchdrugs may be readily ascertained by those of ordinary skill in the artand may include, for instance, antibiotics, other antimalarials,antiinflammatory agents, etc.

[0106] It is understood that the present invention contemplates the useof not only the above-stated trioxolane compounds themselves, but theirprodrugs which metabolize to the compound and the analogues andbiologically active salt forms thereof, as well as optical isomers whichprovide the same pharmaceutical results.

[0107] The following examples are offered to illustrate but not limitthe invention. Thus, they are presented with the understanding thatvarious formulation modifications as well as method of deliverymodifications may be made and still be within the spirit of theinvention.

EXAMPLE 1 General Procedure for the Preparation of 1,2,4-Trioxolanes

[0108] In the priority applications (U.S. Pat. No. 6,486,199 and PCTApp. No. US02/19767, the disclosures of which have been expresslyincorporated by reference), detailed information regarding the synthesisof the starting materials for the OZ compounds was provided. Thisinformation is therefore not repeated herein.

[0109] General procedure for the preparation of 1,2,4-trioxolanes. Ozonewas produced with an OREC ozone generator (0.6 L/min O₂, 60 V), passedthrough an empty gas washing bottle that was cooled to −78° C., andbubbled through a solution of an O-methyl ketone oxime and a ketone inpentane/CH₂Cl₂ at 0° C. The O-methyl oxime of 2-adamantanone wasconsumed within 3 min. After completion, the solution was flushed withoxygen for 5 min before being concentrated in vacuo at room temperatureto give a residue that was purified by crystallization or flashchromatography.

[0110] In the priority applications (U.S. Pat. No. 6,486,199 and PCTApp. No. US0 2/19767), the disclosures of which have been expresslyincorporated by reference), detailed information regarding the synthesisof OZ01-OZ90 has already been provided. This information is thereforenot repeated herein.

[0111]Adamantane-2-spiro-3′-8′-[(1′S)-10′-camphorsulfonyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ91). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol) and1-[(1S)-10-camphorsulfonyl]-4-piperidone (1.56 g, 4.98 mmol) in pentane(50 ml) and CH₂Cl₂ (50 ml) was treated with ozone according to thegeneral procedure. The crude product was purified by flashchromatography (silica gel, 30% ether in hexanes) to afford trioxolaneOZ91 (860 mg, 36%) as a colorless solid. mp 72-74° C. (methanol); ¹H NMR(500 MHz, CDCl₃) δ 0.88 (s, 3H), 1.13 (s, 3H), 1.38-1.51 (m, 1H),1.55-2.21 (m, 22H), 2.32-2.46 (m, 1H), 2.47-2.61 (m, 1H), 2.76 (d,J=14.6 Hz, 1H), 3.35 (d, J=14.6 Hz, 1H), 3.34-3.59 (m, 4H); ¹³C NMR(125.7 MHz, CDCl₃) δ 19.72, 19.94, 25.12, 26.46, 26.84, 26.89, 34.49,34.72, 34.80, 36.40, 36.71, 42.54, 42.91, 43.84, 43.86, 45.84, 47.82,58.25, 106.16, 112.26, 214.78. Anal. Calcd for C₂₅H₃₇NO₆S: C, 62.60; H,7.78; N, 2.92. Found: C, 62.80; H, 7.60; N, 2.92.

[0112]Adamantane-2-spiro-3′-8′-(1′-butanesulfonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ92). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol) and1-(1-butanesulfonyl)-4-piperidone (1.12 g, 5.11 mmol) in pentane (50 ml)and CH₂Cl₂ (50 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 30% ether in hexanes) to afford trioxolane OZ92 (700 mg,36%) as a colorless solid. mp 62-64° C. (methanol); ¹H NMR (500 MHz,CDCl₃) δ0.95 (t, J=7.6 Hz, 3H), 1.32-1.57 (m, 2H), 1.59-2.21 (m, 20H),2.81-3.02 (m, 2H), 3.22-3.59 (m, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ13.48, 21.68, 25.24, 26.50, 26.90, 34.67, 34.78, 34.87, 36.48, 36.75,43.94, 50.09, 106.20, 112.38. Anal. Calcd for C₁₉H₃₁NO₅S: C, 59.19; H,8.10; N, 3.63. Found: C, 59.38; H, 7.99; N, 3.45.

[0113]Adamantane-2-spiro-3′-8′-(phthalimidoacetyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ93). To a solution of OZ87 (342 mg, 1 mmol) in acetonitrile (10 ml)was added potassium phthalimide (200 mg, 1.08 mmol). The reactionsolution was heated at 60-65° C. for 36 h and cooled to rt. The solventwas removed by evaporation, and the residue was triturated with water(20 ml) and filtered. Recrystallization of the solid from methanol gavetrioxolane OZ93 (379 mg, 84%) as a colorless solid. mp 152-154° C.(methanol); ¹H NMR (500 MHz, CDCl₃) δ 1.59-2.11 (m, 18H), 3.45-3.71 (m,3H), 3.72-3.89 (m, 1H), 4.51 (s, 2H), 7.65-7.79 (m, 2H), 7.82-7.97 (m,2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.47, 26.86, 33.94, 34.75, 36.44,36.72, 38.96, 40.38, 42.62, 106.49, 112.36, 123.43, 132.38, 133.93,163.88, 167.87. Anal. Calcd for C₂₅H₂₈N₂O₆: C, 66.36; H, 6.24; N, 6.19.Found: C, 66.19; H, 6.07; N, 6.19.

[0114] Adamantane-2-spiro-3′-1′,2′,4′-trioxolane-5′-spiro-9″-fluorene(OZ94). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol) and9-fluorenone (1.80 g, 10 mmol) in pentane (80 ml) and CH₂Cl₂ (20 ml) wastreated with ozone according to the general procedure. The crude productwas purified by flash chromatography (silica gel, 1% ether in hexanes)to afford trioxolane OZ94 (650 mg, 38%) as a colorless solid. mp150-152° C. (methanol/ether 9:1); ¹H NMR (500 MHz, CDCl₃) δ 1.62-2.25(m, 12H), 2.47 (s, 2 H), 7.27 (dd, J=7.6, 7.6 Hz, 2H), 7.38 (dd, J=7.6,7.6 Hz, 2H), 7.53 (d, J=7.3 Hz, 2H), 7.57 (d, J=7.3 Hz, 2H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.61, 26.99, 34.89, 35.10, 36.51, 36.87, 111.76,112.99, 120.02, 125.22, 128.42, 130.81, 140.29, 140.99. Anal. Calcd forC₂₃H₂₂O₃: C, 79.74; H, 6.40. Found: C, 79.56; H, 6.23.

[0115]Adamantane-2-spiro-3′-5′-(4′-nitrophenyl)-5′-phenyl-1′,2′,4′-trioxolane(OZ95). A solution of O-methyl 2-adamantanone oxime (1.79 g, 10 mmol)and 4-nitrobenzophenone (2.27 g, 10 mmol) in pentane (70 ml) and CH₂Cl₂(80 ml) was treated with ozone according to the general procedure. Thecrude product was purified by flash chromatography (silica gel, 10%ether in hexanes) to afford trioxolane OZ95 (1.60 g, 41%) as a colorlesssolid. mp 114-116° C. (ether); ¹H NMR (500 MHz, CDCl₃) δ 1.60-2.26 (m,14H), 7.32-7.41 (m, 3H), 7.42-7.49 (m, 2H), 7.75 (d, J=8.8 Hz, 2H), 8.22(d, J=8.8 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.46, 26.88, 34.61,34.78, 34.81, 35.42, 36.04, 36.24, 36.71, 108.77, 114.65, 123.37,126.86, 127.62, 128.43, 129.39, 137.62, 148.00, 148.26. Anal. Calcd forC₂₃H₂₃NO₅: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.12; H, 5.66; N,3.58.

[0116]Adamantane-2-spiro-3′-5′,5′-bis(4′-chloro-3′-nitrophenyl)-1′,2′,4′-trioxolane(OZ96). A solution of O-methyl 2-adamantanone oxime (1.79 g, 10 mmol)and 4,4′-dichloro-3,3′-dinitrobenzophenone (2.09 g, 10 mmol) in pentane(80 ml) and CH₂Cl₂ (75 ml) was treated with ozone according to thegeneral procedure. The crude product was purified by flashchromatography (silica gel, 10% ether in hexanes) to afford trioxolaneOZ96 (2.03 g, 40%) as a pale yellow solid. mp 113-115° C. (ether); ¹HNMR (500 MHz, CDCl₃) δ 1.60-2.25 (m, 14H), 7.50-7.71 (m, 4H), 8.04 (d,J=2.0 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.30, 26.68, 34.75, 34.92,36.06, 36.49, 106.72, 116.10, 123.73, 128.27, 131.00, 132.31, 139.19,148.02. Anal. Calcd for C₂₃H₂₀Cl₂N₂O₇: C, 54.45; H, 3.97; N, 5.52.Found: C, 54.46; H, 4.09; N, 5.53.

[0117]Adamantane-2-spiro-3′-8′-phenyl-8′-phthalimidomethyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ97). A solution of O-methyl 2-adamantanone oxime (0.75 g, 4.2 mmol)and 4-phenyl-4-phthalimidomethylcyclohexanone (1.40 g, 4.2 mmol) inpentane (100 ml) and CH₂Cl₂ (50 ml) was treated with ozone according tothe general procedure. The crude product was purified by flashchromatography (silica gel, 12% ethyl acetate in hexanes) to affordtrioxolane OZ97 (0.62 g, 30%) as a colorless solid. mp 150-152° C.(ethanol); ¹H NMR NMR (500 MHz, CDCl₃) δ 1.50-1.99 (m, 20H), 2.40 (appd, J=14.2 Hz, 2H), 3.63 (s, 2H), 7.18-7.30 (m, 1H), 7.31-7.40 (m, 2H),7.41-7.50 (m, 2H), 7.65-7.72 (m, 2H), 7.73-7.85 (m, 2H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.52, 26.88, 30.80, 30.88, 34.79, 36.43, 36.82, 43.90,108.57, 111.33, 123.22, 126.67, 127.10, 128.78, 132.02, 133.84, 141.13,168.44. Anal. Calcd for C₃₁H₃₃NO₅: C, 74.53; H, 6.66; N, 2.80. Found: C,74.54; H, 6.71; N, 2.80.

[0118]Adamantane-2-spiro-3′-8′-methoxycarbonyl-8′-phenyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ98). A solution of O-methyl 2-adamantanone oxime (2.15 g, 12 mmol)and 4-methoxycarbonyl-4-phenylcyclohexanone (2.79 g, 12 mmol) in pentane(100 ml) and CH₂Cl₂ (50 ml) was treated with ozone according to thegeneral procedure. The crude product was purified by flashchromatography (silica gel, 10% ether in hexanes) to afford trioxolaneOZ98 (1.07 g, 22%) as a colorless solid. mp 127-129° C. (ethanol/CH₂Cl₂9:1); ¹H NMR (500 MHz, CDCl₃) δ 1.62-2.15 (m, 20H), 2.53 (app d, J=13.2Hz, 2H), 3.67 (s, 3H), 7.20-7.44 (m, 5H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.54, 26.94, 31.93, 31.98, 34.82, 34.87, 36.48, 36.85, 50.06, 52.22,108.03, 111.58, 125.78, 127.06, 128.59, 142.39, 174.86. Anal. Calcd forC₂₄H₃₀O₅: C, 72.34; H, 7.59. Found: C, 72.12; H, 7.48.

[0119]Adamantane-2-spiro-3′-8′-carboxy-8′-phenyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ99). A mixture of OZ98 (0.42 g, 1.05 mmol), KOH (1.00 g, 17.85 mmol),ethanol (30 ml), THF (25 ml), and water (10 ml) was heated at 50° C. for5 h. The reaction mixture was cooled to rt, concentrated to 10 ml,diluted with water (20 ml), acidified with conc. HCl (2.0 ml), andextracted with CHCl₃ (3×25 ml). The combined extracts were dried overMgSO₄, filtered, and concentrated. Recrystallization of the residue fromhexanes/CH₂Cl₂ (7:3) afforded trioxolane OZ99 (0.31 g, 77%) as acolorless solid. mp 153-156° C. (hexanes/CH₂Cl₂ 7:3); ¹H NMR (500 MHz,CDCl₃) δ 1.62-2.19 (m, 20H), 2.54 (app d, J=11.7 Hz, 2H), 7.20-7.53 (m,5H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.58, 26.98, 31.54, 31.83, 34.84,34.90, 36.51, 36.88, 49.62, 107.96, 111.67, 126.04, 127.34, 128.68,141.44, 180.55. Anal. Calcd for C₂₃H₂₈O₅: C, 71.85; H, 7.34. Found: C,71.66; H, 7.32.

[0120]Adamantane-2-spiro-3′-8′-(4′-pyridinylcarbonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ100). To a solution of OZ80 (225 mg, 0.85 mmol) in CH₂Cl₂ (10 ml) wasadded triethylamine (258 mg, 2.55 mmol). The solution was then cooled to0-5 ° C., and isonicotinoyl chloride hydrochloride (180 mg, 1.01 mmol)was added. The resulting mixture was stirred at rt for 16 h beforeevaporation to dryness. The residue was triturated with water andfiltered. Recrystallization of the solid from methanol at −20° C. gavetrioxolane OZ100 (190 mg, 69%) as a colorless solid. mp 140-142° C.(methanol); ¹H NMR (500 MHz, CDCl₃) δ 1.58-2.16 (m, 18H), 3.31-3.58 (m,2H), 3.68-3.85 (m, 1H), 3.86-4.06 (m, 1H), 7.19-7.37 (m, 2H), 8.60-8.80(m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.47, 26.87, 34.13, 34.76, 34.87,35.18, 36.45, 36.71, 40.03, 45.20, 106.47, 112.49, 120.96, 143.47,150.37, 167.77. Anal. Calcd for C₂₁H₂₆N₂O₄: C, 68.09; H, 7.07; N, 7.56.Found: C, 68.22; H, 7.06; N, 7.68.

[0121]Adamantane-2-spiro-3′-8′-(4′-chlorophenoxyacetyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ101). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol)and 1-(4-chlorophenoxyacetyl)-4-piperidone (1.34 g, 5 mmol) in pentane(50 ml) and CH₂Cl₂ (50 ml) was treated with ozone according to thegeneral procedure. The crude product was purified by flashchromatography (silica gel, 30% ether in hexanes) to afford trioxolaneOZ101 (300 mg, 14%) as a colorless solid. mp 148-150° C. (methanol); ¹HNMR (500 MHz, CDCl₃) δ 1.59-2.19 (m, 18H), 3.48-3.71 (m, 3H), 3.72-3.87(m, 1H), 4.67 (AB system, 2H), 6.80-6.95 (m, 2H), 7.15-7.35 (m, 2H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.47, 26.86, 34.15, 34.75, 34.93, 35.19,36.43, 36.71, 40.21, 43.13, 68.16, 106.54, 112.38, 115.99, 126.80,129.55, 156.57, 166.03. Anal. Calcd for C₂₃H₂₈ClNO₅: C, 63.66; H, 6.50;N, 3.23. Found: C, 63.82; H, 6.46; N, 3.30.

[0122]Adamantane-2-spiro-3′-8′-(phenylaminocarbonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ102). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (101mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0-5° C. was added phenyl isocyanate(140 mg, 1.2 mmol). The reaction mixture was stirred at rt for 3 h,diluted with CH₂Cl₂ (10 ml), and washed with water (10 ml), 10% aq.NaHCO₃(10 ml), 2 M HCl (10 ml), water (10 ml) and brine (10 ml). Theorganic layer was dried over MgSO₄ and concentrated. The residue wastriturated with hexanes (20 ml), filtered, and dried to affordtrioxolane OZ102 (370 mg, 96%) as a colorless solid. mp 146-148° C.(hexanes); ¹H NMR (500 MHz, CDCl₃) δ 1.62-2.11 (m, 18H), 3.42-3.76 (m,4H), 6.46.(s, 1H), 7.04 (dd, J=7.3, 7.3 Hz, 1H), 7.15-7.44 (m, 4H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.52, 26.91, 34.42, 34.80, 34.89, 36.49,36.77, 42.44, 106.80, 112.28, 120.13, 123.29, 128.91, 139.00, 154.88.Anal. Calcd for C₂₂H₂₈N₂O₄: C, 68.73; H, 7.34; N, 7.29. Found: C, 68.78;H, 7.14; N, 7.50.

[0123]Adamantane-2-spiro-3′-8′-(1′H-imidazol-1′-ylacetyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ103). To a solution of OZ87 (342 mg, 1 mmol) in acetonitrile (10 ml)was added imidazole (201 mg, 3 mmol). The mixture was heated at 60-65°C. for 36 h before evaporation to dryness. The crude product waspurified by flash chromatography (silica gel, 5% methanol indichloromethane) and by subsequent recrystallization from hexanes/ether(9:1) to give trioxolane OZ103 (132 mg, 35%) as a colorless solid. mp138-140° C. (hexanes/ether 9:1); ¹H NMR (500 MHz, CDCl₃) δ 1.59-2.21 (m,18H), 3.43-3.60 (m, 2H), 3.61-3.72 (m, 1H), 3.73-3.91 (m, 1H), 4.79 (s,2H), 6.97 (br s, 1H), 7.12 (br s, 1H), 7.52 (br s, 1H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.46, 26.86, 33.98, 34.76, 34.95, 36.44, 36.70, 40.41,43.02, 48.09, 106.22, 112.54, 120.04 (br s), 129.67, 138.10 (br s),164.47. Anal. Calcd for C₂₀H₂₇N₃O₄: C, 64.32; H, 7.29; N, 11.25. Found:C, 64.12; H, 7.02; N, 11.09.

[0124]Adamantane-2-spiro-3′-8′-[[4-(acetylamino)phenyl]sulfonyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ104). To a solution of OZ80 (300 mg, 1 mmol) in CH₂Cl₂ (10 ml) wasadded triethylamine (303 mg, 3 mmol). The solution was then cooled to0-5° C., and 4-acetamidobenzenesulfonyl chloride (280 mg, 1.2 mmol) wasadded. The resulting mixture was stirred at rt for 16 h beforeevaporation to dryness. The residue was triturated with water (15 ml)and filtered. Recrystallization of the solid from methanol/CH₂Cl₂ (9:1)at −20° C. gave trioxolane OZ104 (300 mg, 65%) as a colorless solid. mp122-124° C. (methanol/CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 1.50-2.12 (m,18H), 2.19 (s, 3H), 2.90-3.08 (m, 2H), 3.15-3.37 (m, 2H), 7.65 (d, J=8.8Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.93-8.16 (m, 1H); ¹³C NMR (125.7 MHz,CDCl₃) δ 24.51, 26.46, 26.83, 34.05, 34.74, 34.76, 36.39, 36.70, 44.26,105.86, 112.41, 119.44, 128.73, 131.51, 142.35, 168.72. Anal. Calcd forC₂₃H₃₀N₂O₆S: C, 59.72; H, 6.54; N, 6.06. Found: C, 59.58; H, 6.60; N,5.81.Adamantane-2-spiro-3′-5′,5′-bis(3′-nitrophenyl)-1′,2′,4′-trioxolane(OZ105). A solution of O-methyl 2-adamantanone oxime (1.79 g, 10 mmol)and 3,3′-dinitrobenzophenone (2.72 g, 10 mmol) in pentane (60 ml) andCH₂Cl₂ (40 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 90% ether in hexanes) to afford trioxolane OZ105 (0.90 g,21%) as a colorless solid. mp 131-134° C. (ether); ¹H NMR (500 MHz,CDCl₃) δ 1.60-2.45 (m, 14H), 7.59 (dd, J=7.8, 7.8 Hz, 2H), 7.81-7.88 (m,2H), 8.22-8.28 (m, 2H), 8.41 (dd, J=2.0, 2.0 Hz, 2H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.37, 26.76, 34.77, 34.95, 36.09, 36.58, 107.55, 115.64,121.71, 124.10, 129.67, 132.47, 141.33, 148.46. Anal. Calcd forC₂₃H₂₂N₂O₇: C, 63.01; H, 5.06; N, 6.39. Found: C, 63.26; H, 5.00; N,6.47.

[0125]Adamantane-2-spiro-3′-5′,5′-bis[3′,4′-di(methoxycarbonyl)phenyl]-1′,2′,4′-trioxolane(OZ106). A solution of O-methyl 2-adamantanone oxime (1.79 g, 10 mmol)and 3,3′,4,4′-tetra(methoxycarbonyl)benzophenone (4.14 g, 10 mmol) inpentane (70 ml) and CH₂Cl₂ (80 ml) was treated with ozone according tothe general procedure. The crude product was purified by flashchromatography (silica gel, 80% ether in hexanes) to afford trioxolaneOZ106 (2.03 g, 35%) as a colorless solid. mp 52-54° C. (ether); ¹H NMR(500 MHz, CDCl₃)δ 1.60-2.35 (m, 14H), 3.907 (s, 6H), 3.909 (s, 6H), 7.66(dd, J=8.0, 1.5 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H), 7.87 (d, J=1.5 Hz, 2H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.38, 26.77, 34.75, 34.91, 35.99, 36.62,52.64, 52.66, 107.85, 115.18, 127.10, 129.03, 129.29, 132.05, 132.71,142.41, 167.29, 167.55. Anal. Calcd for C₃₁H₃₂O₁₁: C, 64.13; H, 5.56.Found: C, 64.28; H, 5.46.

[0126]Adamantane-2-spiro-3′-8′-[(aminocarbonyl)oxy]-1′,2′,4′-trioxaspiro[4.5]decane(OZ107). A solution of trichloroacetyl isocyanate (0:44 g, 2.25 mmol)and OZ32 (0.42 g, 1.50 mmol) in CH₂Cl₂ (5 ml) was stirred at 0° C. for 4h. The reaction mixture was warmed up to rt, concentrated, dissolved inmethanol (20 ml), and cooled to 0° C. To this cooled solution was added5% aq. Na₂CO₃ solution (20 ml). The resulting mixture was stirred at 0°C. for 0.1 h, warmed up to rt, and stirred at rt overnight. The reactionsolution was diluted with water (50 ml) and extracted with CHCl₃ (3×40ml). The combined organic layers were washed with water (30 ml) andbrine (30 ml), dried over MgSO₄, and concentrated. Recrystallization ofthe residue from hexanes/chloroform (3:1) gave trioxolane OZ107 (250 mg,52%, 10:1 mixture of two diastereomers) as a colorless solid. mp160-162° C. (hexanes/chloroform 3:1); ¹H NMR (500 MHz, CDCl₃) δ1.50-2.25 (m, 22H), 4.72-4.98 (m, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.52, 26.93, 28.60, 31.01, 34.80, 34.88, 36.39, 36.82, 70.81,107.85,111.69, 156.34. Anal. Calcd for C₁₇H₂₅NO₅: C, 63.14; H, 7.79; N, 4.33.Found: C, 62.91; H, 7.56; N, 4.31.

[0127]cis-Adamantane-2-spiro-3′-8′-(1′-hydroxy-1′-methylethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ108). To a solution of methyllithium (3.80 ml, 1.4 M in ether, 5.4mmol) in ether (5 ml) at −78° C. was added a solution of OZ70 (0.70 g,2.1 mmol) in ether (20 ml). The reaction was stirred at −78° C. for 3 hbefore being quenched with saturated aq. ammonium chloride (20 ml). Themixture was extracted with ether (3×30 ml), and the organic layers werewashed with water (30 ml) and brine (30 ml), dried over MgSO₄, filtered,and concentrated. The crude product was purified by flash chromatography(silica gel, 20% ether in hexanes) to afford trioxolane OZ108 (0.42 g,62%) as a colorless solid. mp 126-128° C. (ethanol/H_(20 4:1)); ¹H NMR(500 MHz, CDCl₃) δ 1.17 (s, 6H), 1.06-1.55 (m, 3H), 1.58-2.30 (m, 20H);¹³C NMR (125.7 MHz, CDCl₃) δ 24.85, 26.59, 26.99, 27.02, 34.50, 34.85,36.50, 36.90, 47.76, 72.51, 108.70, 111.28. Anal. Calcd for C₁₉H₃₀O₄: C,70.77; H, 9.38. Found: C, 70.64; H, 9.15.

[0128]Adamantane-2-spiro-3′-8′-[(3′-carboxypyrazinyl)carbonyl-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ109). To a solution of OZ80 (301 mg, 1 mmol) in CH₂Cl₂ (5 ml) at 0-5°C. were added triethylamine (101 mg, 1 mmol) and2,3-pyrazinedicarboxylic anhydride (156 mg, 1 mmol). The resultingmixture was stirred at rt for 16 h before evaporation to dryness. Theresidue was triturated with water (10 ml) and filtered.Recrystallization of the solid from methanol gave trioxolane OZ109 (300mg, 72%) as a colorless solid. mp 128-130° C. (methanol); ¹H NMR (500MHz, CDCl₃) δ 1.52-2.21 (m, 18H), 3.21-3.43 (m, 2H), 3.79-3.96 (m, 1H),3.97-4.14 (m, 1H), 8.71 (s, 1H), 8.79 (s, 1H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.54, 26.92, 33.73, 34.32, 34.78, 34.83, 34.84, 34.96, 36.48,36.52, 36.79, 39.94, 44.80, 106.79, 112.42, 140.16, 143.16, 146.96,151.73, 163.03, 165.23. Anal. Calcd for C₂₁H₂₅N₃O₆: C, 60.71; H, 6.07;N, 10.11. Found: C, 60.46; H, 5.93; N, 9.96.

[0129]Adamantane-2-spiro-3′-1′,2′,4′-trioxolane-5′-spiro-3″-8″-ethoxycarbonyl-8″-azabicyclo[3.2.1]octane(OZ110). A solution of O-methyl 2-adamantanone oxime (895 mg, 5.0 mmol)and N-carboethoxytropinone (1.01 g, 5.2 mmol) in pentane (80 ml) andCH₂Cl₂ (20 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 15% ether in hexanes) to afford trioxolane OZ110 (300 mg,17%, 2:1 mixture of two diastereomers) as a colorless solid. mp 98-100°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.27 (t, J=7.1 Hz, 3H), 1.58-2.39 (m,22H), 4.15 (q, J=6.8 Hz, 2H), 4.18-4.45 (m, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 14.67, 26.45, 26.50, 26.86, 26.89, 27.16, 27.60 (br s), 33.22,34.68, 34.82, 35.06, 36.37, 36.41, 36.74, 36.77, 37.05, 40.42 (br s),52.44, 52.75, 52.78, 60.88, 60.93, 60.96, 106.98, 107.71, 110.39,112.46, 153.70. Anal. Calcd for C₂₀H₂₉NO₅: C, 66.09; H, 8.04; N, 3.85.Found: C, 66.12; H, 7.90; N, 3.82.

[0130]Adamantane-2-spiro-3′-8′-(3′,3′-dimethylbutanoyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ111). To a solution of OZ80 (302 mg, 1 mmol) in CH₂Cl₂ (10 ml) at0-5° C. were added triethylamine (303 mg, 3 mmol) and trimethylacetylchloride (185 mg, 1.5 mmol). The resulting mixture was stirred at rt for16 h, then diluted with CH₂Cl₂ (10 ml), and washed with water (10 ml)and brine (10 ml). The organic phase was separated, dried over MgSO₄,and concentrated. Crystallization of the residue from methanol gavetrioxolane OZ111 (140 mg, 39%) as a colorless solid. mp 98-100° C.(methanol); ¹H NMR (500 MHz, CDCl₃) δ 1.05 (s, 9H), 1.58-2.11 (m, 18H),2.27 (AB system, 2H), 3.46-3.69 (m, 3H), 3.75-3.90 (m, 1H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.60, 26.99, 30.06, 31.39, 34.37 (br s), 34.85,35.34 (br s), 36.57, 36.85, 39.44 (br s), 44.40 (br s), 44.75, 106.92,112.25, 170.30. Anal. Calcd for C₂₁H₃₃NO₄: C, 69.39; H, 9.15; N, 3.85.Found: C, 69.52; H, 8.89; N, 3.72.

[0131]Adamantane-2-spiro-3′-8′-[(carboxymethoxy)acetyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ112). To a solution of OZ80 (302 mg, 1 mmol) in CH₂Cl₂ (10 ml) wasadded triethylamine (101 mg, 1 mmol). The solution was then cooled to0-5° C., and diglycolic anhydride (116 mg, 1 mmol) was added. Theresulting mixture was stirred at rt for 16 h before evaporation todryness. The residue was triturated with water (10 ml) and filtered.Recrystallization of the solid from methanol gave trioxolane OZ112 (250mg, 66%) as a colorless solid. mp 126-128° C. (methanol); ¹H NMR (500MHz, CDCl₃). 1.59-2.18 (m, 18H), 3.29-3.49 (m, 2H), 3.63-3.77 (m, 1H),3.79-3.91 (m, 1H), 4.22 (s, 2H), 4.42 (s, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.44, 26.84, 33.91, 34.72, 34.80, 34.97, 36.45, 36.68, 40.56,42.21, 70.94, 72.00, 106.08, 112.64, 169.20, 171.40. Anal. Calcd forC₁₉H₂₇NO₇: C, 59.83; H, 7.14; N, 3.67. Found: C, 59.67; H, 7.16; N,3.56.

[0132]Adamantane-2-spiro-3′-8′-methoxyacetyl-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ113). To a solution of OZ80 (301 mg, 1 mmol) in CH₂Cl₂ (10 ml) wasadded triethylamine (303 mg, 3 mmol). The solution was then cooled to0-5° C., and methoxyacetyl chloride (163 mg, 1.5 mmol) was added. Theresulting mixture was stirred at rt for 16 h and washed with water (5ml) and brine (5 ml). The organic phase was separated, dried over MgSO₄,and concentrated to give trioxolane OZ113 (325 mg, 96%) as a colorlesssolid. mp 76-78° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.59-2.17 (m, 18H), 3.42(s, 3H), 3.43-3.73 (m, 3H), 3.75-3.89 (m, 1H), 4.11 (AB system, 2H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.57, 26.97, 34.32 (br s), 34.83, 34.92, 35.25(br s), 36.55, 36.82, 39.98 (br s), 42.87 (br s), 58.96, 72.21, 106.78,112.30, 167.54. Anal. Calcd for C₁₈H₂₇NO₅: C, 64.07; H, 8.07; N, 4.15.Found: C, 63.94; H, 8.03; N, 4.30.

[0133]Adamantane-2-spiro-3′-8′-(8′-quinolinesulfonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ114). To a solution of OZ80 (151 mg, 0.5 mmol) in CH₂Cl₂ (5 ml) wasadded triethylamine (150 mg, 1.49 mmol). The solution was then cooled to0-5° C., and 8-quinolinesulfonyl chloride (115 mg, 0.5 mmol) was added.The resulting mixture was stirred at rt for 12 h before evaporation todryness. The residue was triturated with water (5 ml) and filtered.Recrystallization of the solid from methanol gave trioxolane OZ114 (215mg, 94%) as a colorless solid. mp 142-144° C. (methanol); ¹H NMR (500MHz, CDCl₃) δ 1.55-2.21 (m, 18H), 3.40-3.61 (m, 2H), 3.62-3.85 (m, 2H),7.51 (dd, J=8.2, 3.9 Hz, 1H), 7.61 (dd, J=8.2, 8.2 Hz, 1H), 8.02 (d,J=7.8 Hz, 1H), 8.23 (dd, J=8.3, 1.5 Hz, 1H), 8.47 (dd, J=7.3, 1.5 Hz,1H), 9.05 (dd, J=3.9, 1.5 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.58,26.97, 34.82, 34.88, 34.90, 36.54, 36.83, 44.37, 106.74, 112.16, 121.98,125.47, 129.12, 132.68, 133.24, 136.30, 137.86, 144.33, 151.10. Anal.Calcd for C₂₄H₂₈N₂O₅S: C, 63.14; H, 6.18; N, 6.14. Found: C, 62.94; H,6.16; N, 6.00.

[0134]Adamantane-2-spiro-3′-8′-(1′-octanesulfonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ115). To a solution of OZ80 (200 mg, 0.66 mmol) and triethylamine(200 mg, 1.98 mmol) in CH₂Cl₂ (5 ml) at 0-5° C. was added1-octanesulfonyl chloride (170 mg, 0.8 mmol). The resulting mixture wasstirred at rt for 12 h before evaporation to dryness. The residue wastriturated with water (10 ml) and filtered. Recrystallization of thesolid from methanol gave trioxolane OZ115 (160 mg, 55%) as a colorlesssolid. mp 54-56° C. (methanol); ¹H NMR (500 MHz, CDCl₃) δ 0.88 (t, J=6.8Hz, 3H), 1.17-1.49 (m, 10H), 1.61-2.21 (m, 20H), 2.90 (t, J=8.1 Hz, 2H),3.24-3.39 (m, 2H), 3.41-3.57 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ13.95, 22.56, 23.26, 26.55, 26.95, 28.49, 28.93, 29.04, 31.71, 34.71,34.82, 34.91, 36.53, 36.79, 43.97, 50.46, 106.24, 112.41. Anal. Calcdfor C₂₃H₃₉NO₅S: C, 62.55; H, 8.90; N, 3.17. Found: C, 62.38; H, 8.76; N,3.25.,

[0135]cis-Adamantane-2-spiro-3′-8′-[(hydroxyamino)carbonyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ116). A solution of ethyl chloroformate (0.26 g, 2.4 mmol), OZ72(0.62 g, 2.0 mmol), and triethylamine (0.27 g, 2.6 mmol) in ether (6 ml)was stirred at 0° C. for 10 min. The solid was removed by filtration,and the filtrate was added to a freshly prepared solution ofhydroxylamine. [To a suspension of KOH (168 mg, 3.0 mmol) in methanol (1ml) at 0° C. was added a solution of hydroxylamine hydrochloride (0.20g, 3 mmol) in methanol (3 ml). The reaction mixture was stirred at 0° C.for 15 min and filtered to remove solid by-products. The filtrate wasused as such.] The resulting mixture was stirred at rt for 1 h andconcentrated. The crude product was purified by flash chromatography(silica gel, 8% methanol in chloroform) to afford trioxolane OZ116 (0.23g, 36%) as a colorless solid. mp 130-132° C. (ethanol/water 1:2); ¹H NMR(500 MHz, DMSO-d₆) δ 1.40-2.19 (m, 23H), 8.60 (s, 1H), 10.35 (s, 1H);¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.87, 26.27, 26.50, 33.03, 34.28, 34.30,35.84, 36.15, 39.04, 107.85, 110.64, 171.30. Anal. Calcd for C₁₇H₂₅NO₅:C, 63.14; H, 7.79; N, 4.33. Found: C, 62.97; H, 7.57; N, 4.26.

[0136]Adamantane-2-spiro-3′-8′-(aminomethyl)-8′-phenyl-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ117). A solution of OZ97 (1.60 g, 3.2 mmol) andhydrazine monohydrate (325 mg, 6.5 mmol) in chloroform (27 ml) andmethanol (3 ml) was heated at 50° C. for 36 h. The reaction mixture wascooled to rt and filtered to remove solid by-products. The filtrate waswashed with water (20 ml) and brine (20 ml), dried over MgSO₄, filtered,and concentrated. The solid was dissolved in ether (30 ml), treated with1 M ethereal HCl (6 ml), and filtered. Recrystallization fromhexanes/chloroform (2:1) gave trioxolane OZ117 (0.22 g, 17%) as acolorless solid. mp 156° C. dec (hexanes/chloroform 2:1); ¹H NMR (500MHz, DMSO-d₆) δ 1.42-2.05 (m, 20H), 2.32 (apparent d, J=13.7 Hz, 2H),2.89 (s, 2H), 7.26-7.39 (m, 1H), 7.41-7.62 (m, 4H), 7.80 (br s, 3H); ¹³CNMR (125.7 MHz, DMSO-d₆) δ 25.82, 26.19, 30.08, 34.24, 35.76, 36.09,49.37, 107.89, 110.70, 126.97, 127.14, 128.98, 139.82. Anal. Calcd forC₂₃H₃₂ClNO₃: C, 68.05; H, 7.95; N, 3.45. Found: C, 67.92; H, 7.69; N,3.72.

[0137]cis-Adamantane-2-spiro-3′-8′-acetoxymethyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ118). A solution of O-methyl 2-adamantanone oxime (1.34 g, 7.5 mmol)and 4-acetoxymethylcyclohexanone (1.28 g, 7.5 mmol) in pentane (100 ml)and CH₂Cl₂ (20 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 10% ether in hexanes) to afford trioxolane OZ118 (1.15 g,46%) as a colorless solid. mp 39-41° C. (ethanol/H_(20 7:3)); ¹H NMR(500 MHz, CDCl₃) δ 1.18-1.31 (m, 2H), 1.59-2.19 (m, 21H), 2.05 (s, 3H),3.90 (d, J=6.3 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 20.77, 26.62,26.77, 27.02, 33.71, 34.86, 34.88, 35.67, 36.54, 36.91, 68.49, 108.57,111.40, 170.90. Anal. Calcd for C₁₉H₂₈O₅: C, 67.83; H, 8.39. Found: C,67.70; H, 8.32.

[0138]cis-Adamantane-2-spiro-3′-8′-hydroxymethyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ119). A solution of OZ70 (0.81 g, 2.4 mmol), lithium borohydride (1.2ml, 2.4 mmol, 2 M in THF), and lithium triethylborohydride (0.24 ml,0.24 mmol, 1 M in THF) in ether (2.5 ml) was stirred at rt for 3 h. Thereaction mixture was diluted with ether (5 ml), washed with 3 M aq. NaOH(2×5 ml), water (2×5 ml) and brine (5 ml), dried over MgSO₄, filtered,and concentrated in vacuo to afford trioxolane OZ119 (0.68 g, 96%) as acolorless solid. mp 97-99° C. (ethanol/H₂O 1:1); ¹H NMR (500 MHz, CDCl₃)δ 1.09-1.27 (m, 2H), 1.42-2.19 (m, 21H), 3.47 (d, J=6.5 Hz, 2H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.63, 26.66, 27.03, 33.86, 34.87, 34.90, 36.56,36.93, 38.97, 67.63, 108.91, 111.32. Anal. Calcd for C₁₇H₂₆O₄: C, 69.36;H, 8.90. Found: C, 69.58; H, 8.63.

[0139]Adamantane-2-spiro-3′-11′,11′-bis(ethoxycarbonyl)-1′,2′,4′,9′,13′-pentaoxadispiro[4.2.5.2]pentadecane(OZ120). A solution of O-methyl 2-adamantanone oxime (2.69 g, 15 mmol)and 3,3-bis(ethoxycarbonyl)-1,5-dioxaspiro[5.5]undecan-9-one (4.71 g, 15mmol) in pentane (100 ml) and CH₂Cl₂ (50 ml) was treated with ozoneaccording to the general procedure. The crude product was purified byflash chromatography (silica gel, 10% ether in petroleum ether) toafford trioxolane OZ120 (3.60 g, 50%) as a colorless solid. mp 74-77° C.(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.27 (t, J=7.1 Hz, 6H), 1.61-2.18(m, 22H), 4.24 (q, J=7.2 Hz, 4H), 4.28 (s, 4H); ¹³C NMR (125.7 MHz,CDCl₃) δ 13.91, 26.55, 26.95, 29.35, 30.45, 34.77, 34.87, 36.43, 36.83,39.26, 53.95, 61.77, 62.10, 97.54, 108.22, 111.56, 167.84. Anal. Calcdfor C₂₅H₃₆O₉: C, 62.48; H, 7.55. Found: C, 62.62; H, 7.32.

[0140]Adamantane-2-spiro-3′-11′,11′-bis(hydroxymethyl)-1′,2′,4′,9′,13′-pentaoxadispiro[4.2.5.2]pentadecane(OZ121). A solution of OZ120 (1.00 g, 2.18 mmol), lithium borohydride(2.10 ml, 4.20 mmol, 2 M in THF), and lithium triethylborohydride (0.42ml, 0.42 mmol, 1 M in THF) in ether (5 ml) was stirred at rt for 3 h.The reaction mixture was diluted with ether (10 ml) and washed with 3 Maq. NaOH (2×10 ml), water (2×10 ml), and brine (10 ml). The combinedaqueous layers were extracted with CHCl₃ (3×50 ml), and the chloroformextract was washed with water (2×50 ml) and brine (50 ml). The etherextract and chloroform extract were combined, dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 5% methanol in chloroform) to affordtrioxolane OZ121 (0.40 g, 46%) as a colorless solid. mp 146-148° C.(ethanol/H_(20 3:2)); ¹H NMR (500 MHz, DMSO-d₆) δ 1.60-2.15 (m, 22H),3.36 (d, J=4.9 Hz, 4H), 3.61 (s, 2H), 3.62 (s, 2H), 4.49 (t, J=5.4 Hz,2H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.86, 26.26, 29.34, 30.21, 34.27,34.36, 35.77, 36.13, 39.07, 60.69, 61.44, 61.48, 96.00, 108.15, 110.84.Anal. Calcd for C₂₁H₃₂O₇.0.077CHCl₃: C, 62.40; H, 7.97. Found: C, 62.76;H, 7.77.

[0141]Adamantane-2-spiro-3′-11′,11′-dicarboxy-1′,2′,4′,9′,13′-pentaoxadispiro[4.2.5.2]pentadecane(OZ122). A solution of OZ120 (0.73 g, 1.5 mmol), 15% aq. KOH (4.2 ml) inmethanol (30 ml) was heated at 50° C. for 2 h. After being cooled to rt,the reaction mixture was concentrated to 5 ml, acidified with conc. HCl,and extracted with CHCl₃ (5×50 ml). The combined organic layers werewashed with water (2×50 ml) and brine (50 ml), dried over MgSO₄,filtered, and concentrated to afford trioxolane OZ122 (0.38 g, 58%) as acolorless solid. mp 151-153° C. (water); ¹H NMR (500 MHz, DMSO-d₆) δ1.51-2.14 (m, 22H), 4.13 (s, 2H), 4.15 (s, 2H); ¹³C NMR (125.7 MHz,DMSO-d₆) δ 25.86, 26.26, 29.16, 30.16, 34.27, 34.37, 35.77, 36.13,52.89, 61.65, 96.49, 107.99, 110.92, 169.11. Anal. Calcd for C₂₁H₂₈O₉:C, 59.43; H, 6.65. Found: C, 59.42; H, 6.66.

[0142]cis-Adamantane-2-spiro-3′-8′-bromomethyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ123). A solution of O-methyl 2-adamantanone oxime (2.15 g, 12 mmol)and 4-bromomethylcyclohexanone (2.30 g, 12 mmol) in pentane (100 ml) andCH₂Cl₂ (50 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 3% ether in hexanes) to afford trioxolane OZ123 (1.62 g,38%) as a colorless solid. mp 138-140° C. (ethanol); ¹H NMR (500 MHz,CDCl₃) δ 1.21-1.41 (m, 2H), 1.51-2.21 (m, 21H), 3.28 (d, J=6.3 Hz, 2H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.64, 27.04, 28.83, 33.73, 34.88, 34.90,36.55, 36.93, 38.63, 38.76, 108.41, 111.47. Anal. Calcd for C₁₇H₂₅BrO₃:C, 57.15; H, 7.05. Found: C, 57.20; H, 6.99.

[0143]Adamantane-2-spiro-3′-5′-(4′-cyanophenyl)-5′-phenyl)-1′,2′,4′-trioxolane(OZ124). A solution of O-methyl 2-adamantanone oxime (0.86 g, 4.80 mmol)and 4-cyanobenzophenone (1.00 g, 4.80 mmol) in pentane (50 ml) andCH₂Cl₂ (60 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 10% ether in hexanes) to afford trioxolane OZ124 (0.30 g,17%) as a colorless solid. mp 136-137° C. (ether); ¹H NMR (500 MHz,CDCl₃) δ 1.60-2.35 (m, 14H), 7.31-7.39 (m, 3H), 7.40-7.48 (m, 2H),7.62-7.73 (m, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.50, 26.92, 34.70,34.80, 34.84, 35.39, 36.08, 36.25, 36.76, 108.84, 112.50, 114.57,118.43, 126.85, 127.42, 128.38, 129.27, 131.97, 137.97, 146.30. Anal.Calcd for C₂₄H₂₃NO₃: C, 77.19; H, 6.21; N, 3.75. Found: C, 77.58; H,6.32; N, 3.76.

[0144]Adamantane-2-spiro-3′-5′,5′-bis[4′-(ethoxycarbonyl)phenyl]-1′,2′,4′-trioxolane(OZ125). A solution of O-methyl 2-adamantanone oxime (1.79 g, 10 mmol)and 4,4′-bis(ethoxycarbonyl)benzophenone (3.26 g, 10 mmol) in pentane(60 ml) and CH₂Cl₂ (40 ml) was treated with ozone according to thegeneral procedure. The crude product was purified by flashchromatography (silica gel, 10% ether in hexanes) to afford trioxolaneOZ125 (1.77 g, 36%) as a colorless solid. mp 143-145° C. (ether); ¹H NMR(500 MHz, CDCl₃) δ 1.38 (t, J=7.1 Hz, 6H), 1.60-2.07 (m, 12H), 2.20 (appd, J=12.2 Hz, 2H), 4.37 (q, J=7.2 Hz, 4H), 7.58 (d, J=8.3 Hz, 4H), 8.03(d, J=8.3 Hz, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ 14.28, 26.52, 26.94,34.84, 35.06, 36.17, 36.78, 61.01, 108.84, 114.60, 126.69, 129.52,131.10, 144.22, 166.06. Anal. Calcd for C₂₉H₃₂O₇: C, 70.71; H, 6.55.Found: C, 70.52; H, 6.32.

[0145]cis-Adamantane-2-spiro-3′-8′-[2′-(diethylamino)ethyl]-1′,2′,4′-trioxaspiro[4.5]decanehydrobromide (OZ126). Step 1. A solution of O-methyl 2-adamantanoneoxime (716 mg, 4 mmol) and 4-(2-bromoethyl)cyclohexanone (820 mg, 4mmol) in pentane (72 ml) and CH₂Cl₂ (8 ml) was treated with ozoneaccording to the general procedure. The crude product was purified byflash chromatography (silica gel, 1% ether in hexanes) to affordcis-Adamantane-2-spiro-3′-8′-(2′-bromoethyl)-1′,2′,4′-trioxaspiro[4.5]decane(800 mg, 54%) as a colorless solid. mp 62-64° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.18-1.22 (m, 2H), 1.72-2.10 (m, 23H), 3.42 (t, 2H, J=6.8 Hz).Step 2. To a solution of the above bromide (371 mg, 1 mmol) inacetonitrile (5 ml) were added diethylamine (140 mg, 2 mmol) andtriethylamine (101 mg, 1 mmol). The mixture was heated at 60-65° C. for60 h before removal of solvents. The residue was triturated with water(5 ml) and filtered. Recrystallization of the solid from ethanol gavetrioxolane OZ126 (170 mg, 43%) as a colorless solid. mp 152-154° C.(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.20-1.34 (m, 2H), 1.41 (t, J=7.3Hz, 6H), 1.60-2.25 (m, 23H), 2.95-3.04 (m, 2H), 3.05-3.19 (m, 4H), 12.17(s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 8.69, 26.61, 27.00, 29.13, 29.84,33.90, 34.34, 34.86, 34.88, 36.54, 36.90, 46.55, 49.51, 108.27, 111.54.Anal. Calcd for C₂₂H₃₇NO₃.0.5HBr: C, 65.41; H, 9.36; N, 3.47. Found: C,65.24; H, 9.54; N, 3.46.

[0146]trans-Adamantane-2-spiro-3′-8′-[(hydroxyamino)carbonyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ127). A solution of ethyl chloroformate (0.13 g, 1.2 mmol), OZ71(0.31 g, 1.0 mmol), and triethylamine (0.13 g, 1.3 mmol) in ether (5 ml)was stirred at 0° C. for 10 min. The solid was removed by filtration,and the filtrate was added to a freshly prepared solution ofhydroxylamine. [To a suspension of KOH (84 mg, 1.5 mmol) in methanol (1ml) at 0° C. was added a solution of hydroxylamine hydrochloride (0.10g, 1.5 mmol) in methanol (2 ml). The reaction mixture was stirred at 0°C. for 15 min and filtered to remove solid by-products. The filtrate wasused as such.] The resulting mixture was stirred at rt for 1 h andconcentrated. The crude product was purified by crystallization fromhexanes/chloroform (5:1) to afford trioxolane OZ127 (0.15 g, 47%) as acolorless solid. mp 136-138° C. (hexanes/chloroform 5:1); ¹H NMR (500MHz, DMSO-d₆) δ 1.42-2.23 (m, 23H), 8.60 (s, 1H), 10.36 (s, 1H); ¹³C NMR(125.7 MHz, DMSO-d₆) δ 25.87, 26.26, 26.40, 32.95, 34.26, 34.42, 35.81,36.13, 39.26, 107.88, 110.95, 171.35. Anal. Calcd for C₁₇H₂₅NO₅: C,63.14; H, 7.79; N, 4.33. Found: C, 62.89; H, 7.59; N, 4.40.

[0147]Adamantane-2-spiro-3′-11′-methylene-1′,2′,4′,9′,13′-pentaoxadispiro[4.2.5.2]pentadecane(OZ128). Step 1. A mixture of OZ05 (1.12 g, 4 mmol), TFA (0.70 ml),CH₂Cl₂ (10 ml), and methanol (70 ml) was stirred at rt for 16 h. Thereaction was quenched with NaHCO₃ (2.0 g) and stirred for additional 1 hbefore evaporation to dryness. The residue was dissolved in CH₂Cl₂ (20ml), washed with water and brine, dried over MgSO₄, filtered, andconcentrated to afford dimethyl ketal of OZ05 (1.31 g, 100%) as acolorless oil. ¹H NMR (500 MHz, CDCl₃) δ 1.66-2.02 (m, 22H), 3.18 (s,3H), 3.19 (s, 3H). Step 2. A mixture of the above ketal (1.30 g, 4mmol), 2-methylene-1,3-propanediol (0.70 g, 8 mmol), and p-TsOH (0.5 g)in CH₂Cl₂ (70 ml) and THF (10 ml) was stirred at rt for 16 h. Thereaction was quenched with NaHCO₃ (1.0 g), stirred for additional 1 h,and diluted with water (70 ml). After separation of the organic layer,the aqueous layer was extracted with CH₂Cl₂ (2×50 ml). The combinedorganic layers were washed with water and brine, dried over MgSO₄,filtered, and concentrated. The crude product was purified by flashchromatography (silica gel, 8% ether in hexanes) to afford trioxolane128 (0.87 g, 63%) as a colorless solid. mp 58-59° C. (hexanes); ¹H NMR(500 MHz, CDCl₃) δ 1.59-2.21 (m, 22H), 4.31 (s, 4H), 4.86 (s, 2H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.60, 27.02, 29.97, 30.69, 34.84, 34.94,36.49, 36.90, 63.63, 97.60, 107.92, 108.38, 111.59, 141.15. Anal. Calcdfor C₂₀H₂₈O₅: C, 68.94; H, 8.10. Found: C, 68.77; H, 7.93.

[0148]cis-Adamantane-2-spiro-3′-8′-[(2′-hydroxy-1′,1′-dimethylethylamino)carbonyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ129). A solution of OZ72 (0.77 g, 2.50 mmol), DCC (0.78 g, 3.75mmol), HOBT (0.51 g, 3.75 mmol), and 2-amino-2-methyl-1-propanol (0.33g, 3.75 mmol) in DMF (20 ml) was heated at 50-60° C. for 6 h. Afterbeing cooled to rt, the reaction mixture was acidified with 1 M aq. HCl(100 ml) and extracted with ethyl acetate (4×60 ml). The combinedextracts were washed with water and brine, dried over MgSO₄, filtered,and concentrated. The crude product was purified by flash chromatography(silica gel, 50% ethyl acetate in hexanes) to afford trioxolane 129(0.44 g, 46%) as a colorless solid. mp 163-164° C. (ethanol); ¹H NMR(500 MHz, CDCl₃) δ 1.27 (s, 6H), 1.60-2.24 (m, 23H), 3.56 (s, 2H), 4.80(s, 1H), 5.47 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 24.77, 26.62, 27.03,27.21, 33.64, 34.86, 34.90, 36.55, 36.91, 44.24, 55.95, 70.66, 107.78,111.60, 175.63. Anal. Calcd for C₂₁H₃₃NO₅: C, 66.46; H, 8.76; N, 3.69.Found: C, 66.41; H, 8.56; N, 3.76.

[0149]Adamantane-2-spiro-3′-11′-oxo-1′,2′,4′,9′,13′-pentaoxadispiro[4.2.5.2]pentadecane(OZ130). A solution of OZ128 (0.65 g, 1.9 mmol) in CH₂Cl₂ (80 ml) at−78° C. was treated with ozone for 10 min, flashed with oxygen for 5 minbefore addition of triphenylphosphine (0.49 g, 1.9 mmol). The reactionmixture was warmed up to rt and stirred at rt for 1 h before evaporationto dryness. The crude product was purified by flash chromatography(silica gel, 10% ether in hexanes) to afford trioxolane OZ130 (0.37 g,57%) as a colorless solid. mp 76-79° C. (hexanes); ¹H NMR (500 MHz,CDCl₃) δ 1.61-2.21 (m, 22H), 4.17 (s, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.61, 27.03, 29.80, 30.81, 34.85, 34.96, 36.52, 36.89, 66.92, 66.94,99.14, 107.96, 111.82, 207.00. Anal. Calcd for C₁₉H₂₆O₆: C, 65.13; H,7.48. Found: C, 65.38; H, 7.58.

[0150]Adamantane-2-spiro-3′-8′-phenylmethanesulfonyl-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ131). To a solution of OZ80 (301 mg, 1.0 mmol) and p-toluenesulfonylchloride (192 mg, 1.0 mmol) in CH₂Cl₂ (10 ml) at 0-5° C. was addedtriethylamine (303 mg, 3.0 mmol). The resulting mixture was stirred atrt for 16 h before evaporation to dryness. The residue was trituratedwith water, filtered, and crystallized from ethanol to give trioxolaneOZ131 (320 mg, 76%) as a colorless solid. mp 148-150° C. (ethanol); ¹HNMR (500 MHz, CDCl₃) δ 1.59-2.21 (m, 18H), 3.06-3.24 (m, 2H), 3.25-3.41(m, 2H), 4.22 (s, 2H), 7.27-7.60 (m, 5H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.53, 26.94, 34.77, 34.79, 34.89, 36.50, 36.78, 44.20, 57.79, 106.20,112.28, 128.79, 129.12, 130.67. Anal. Calcd for C₂₂H₂₉NO₅S: C, 62.98; H,6.97; N, 3.34. Found: C, 63.16; H, 6.79; N, 3.46.

[0151]Adamantane-2-spiro-3′-8′-(2′-carboxybenzoyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ132). To a solution of OZ80 (301 mg, 1.0 mmol) and triethylamine (101mg, 1.0 mmol) in CH₂Cl₂ (10 ml) at 0-5° C. was added phthalic anhydride(148 mg, 1.0 mmol). The resulting mixture was stirred at rt for 24 hbefore evaporation to dryness. The residue was triturated, filtered, andcrystallized from ethanol to give trioxolane OZ132 (285 mg, 69%) as acolorless solid. mp 162-164° C. (ethanol); ¹H NMR (500 MHz, DMSO-d₆) δ1.57-2.21 (m, 18H), 3.01-3.32 (m, 2H), 3.354.04 (m, 2H), 7.33 (d, J=7.3Hz, 1H), 7.52 (dd, J=7.8, 7.8 Hz, 1H), 7.64 (dd, J=7.3, 7.3 Hz, 1H),7.93 (d, J=7.8 Hz, 1H), 13.14 (br s, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ25.84, 26.23, 33.29, 33.54, 34.25, 34.34, 35.74, 35.79, 36.07, 38.82,44.26, 107.05, 111.35, 126.62, 128.43, 128.63, 130.03, 132.42, 138.38,166.90, 168.45. Anal. Calcd for C₂₃H₂₇NO₆: C, 66.81; H, 6.58; N, 3.39.Found: C, 67.02; H, 6.65; N, 3.40.

[0152]Adamantane-2-spiro-3′-8′-[(dimethylamino)carbonyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ133). To a solution of OZ80 (301 mg, 1.0 mmol) and triethylamine (101mg, 1.0 mmol) in CH₂Cl₂ (10 ml) at 0-5° C. was added dimethylcarbamoylchloride (115 mg, 1.07 mmol). The resulting mixture was stirred at rtfor 16 h before evaporation to dryness. The residue was triturated, andfiltered, and crystallized from methanol to give trioxolane OZ133 (260mg, 77%) as a colorless solid. mp 106-108° C. (methanol); ¹H NMR (500MHz, CDCl₃) δ 1.60-2.11 (m, 18H), 2.82 (s, 6H), 3.21-3.47 (m, 4H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.61, 27.01, 34.52, 34.84, 34.94, 36.59,36.87, 38.53, 44.69, 107.28, 111.95, 164.66. Anal. Calcd for C₁₈H₂₈N₂O₄:C, 64.26; H, 8.39; N, 8.33. Found: C, 64.49; H, 8.36; N, 8.42.

[0153] Adamantane-2-spiro-3′-1′,2′,4′-trioxolane-5′-spiro-4″-2″,3″-dihydro-4″H-1″-benzopyran (OZ134). A solution of O-methyl2-adamantanone oxime (895 mg, 5 mmol) and 4-chromanone (740 mg, 5 mmol)in cyclohexane (80 ml) and CH₂Cl₂ (20 ml) was treated with ozoneaccording to the general procedure. The crude product was purified byflash chromatography (silica gel, 2% ether in hexanes) to affordtrioxolane OZ134 (590 mg, 38%) as a colorless solid. mp 136-138° C.(methanol); ¹H NMR (500 MHz, CDCl₃) δ 1.61-2.38 (m, 14H), 2.39-2.61 (m,2H), 4.234.51 (m, 2H), 6.83 (d, J=8.3 Hz, 1H), 6.96 (dd, J=8.3, 8.3 Hz,1H), 7.27 (ddd, J=8.6, 8.6, 1.6 Hz, 1H), 7.53 (dd, J=7.8, 1.6 Hz, 1H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.61, 27.03, 33.46, 33.97, 34.89, 34.94,35.78, 36.43, 36.91, 37.08, 64.65, 103.93, 112.95, 117.04, 120.68,128.26, 131.42, 157.71. Anal. Calcd for C₁₉H₂₂O₄: C, 72.59; H, 7.05.Found: C, 72.48; H, 6.87.

[0154]Adamantane-2-spiro-3′-5′,5′-bis(4′-carboxyphenyl)-1′,2′,4′-trioxolane(OZ135). A mixture of OZ125 (0.44 g, 0.89 mmol), THF (7 ml), and 40% aq.KOH (4.5 ml) was heated at 50° C. for 5 days. The reaction mixture wascooled to rt and extracted with ether (5×20 ml). The aqueous layer wasacidified to pH=3 with conc. HCl. The resulting precipitate was filteredand recrystallized from ethanol/water (2:1) to afford trioxolane OZ135(0.35 g, 90%) as a colorless solid. mp 170° C. (EtOAc) dec; ¹H NMR (500MHz, CDCl₃) δ 1.60-2.05 (m, 12H), 2.13 (app d, J=11.7 Hz, 2H), 7.60 (d,J=8.8 Hz, 4H), 7.98 (d, J=8.8 Hz, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ25.79, 26.19, 34.25, 34.42, 35.56, 35.99, 108.40, 113.95, 126.42,129.46, 131.47, 143.44, 166.69. Anal. Calcd for C₂₅H₂₄O₇: C, 68.80; H,5.54. Found: C, 68.64; H, 5.34.

[0155]cis-Adamantane-2-spiro-3′-8′-phthalimido-1′,2′,4′-trioxaspiro[4.5]decane(OZ136). A solution of O-methyl 2-adarmantanone oxime (1.79 g, 10 mmol)and 4-phthalimidocyclohexanone (2.43 g, 10 mmol) in pentane (60 ml) andCH₂Cl₂ (80 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 80% ether in hexanes) to afford trioxolane OZ136 (1.20 g,29%) as a colorless solid. mp 156-158° C. (ether); ¹H NMR NMR (500 MHz,CDCl₃) δ 1.60-2.19 (m, 20H), 2.45-2.63 (m, 2H), 4.18 (tt, J=12.4, 3.9Hz, 1H), 7.64-7.76 (m, 2H), 7.77-7.89 (m, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.60, 26.89, 27.00, 33.81, 34.85, 36.45, 36.89, 49.35, 107.43,111.50, 123.06, 132.13, 133.75, 168.01. Anal. Calcd for C₂₄H₂₇NO₅: C,70.40; H, 6.65; N, 3.42. Found: C, 70.16; H, 6.43; N, 3.43.

[0156]cis-Adamantane-2-spiro-3′-8′-amino-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ137). A solution of OZ136 (0.81 g, 1.98 mmol) andhydrazine monohydrate (198 mg, 3.96 mmol) in chloroform (16 ml) andmethanol (2 ml) was heated under nitrogen at 50° C. for 24 h. Thereaction mixture was cooled to rt, filtered to remove solid by-products,and concentrated. The solid residue was dissolved in CHCl₃, washed withwater and brine, dried over MgSO₄, filtered, and concentrated. The oilyamine was dissolved in ether (2 ml), treated with 1 M ethereal HCl (7ml), and filtered to give trioxolane OZ137 (0.31 g, 50%) as a colorlesssolid. mp 132° C. dec (ether); ¹H NMR (500 MHz, DMSO-d₆) δ 1.41-1.59 (m,2H), 1.60-2.15 (m, 20H), 3.10 (br s, 1H), 8.12 (br s, 3H); ¹³C NMR(125.7 MHz, DMSO-d₆) δ 25.83, 26.23, 27.46, 31.33, 34.27, 34.30, 35.73,36.10, 47.31, 107.24, 110.96. Anal. Calcd for C₁₆H₂₆ClNO₃: C, 60.85; H,8.30; N, 4.43. Found: C, 60.64; H, 8.16; N, 4.70.

[0157]Adamantane-2-spiro-3′-5′-[4′-(methoxycarbonyl)phenyl]-5′-phenyl-1′,2′,4′-trioxolane(OZ138). A solution of O-methyl 2-adamantanone oxime (1.79 g, 10 mmol)and 4-(methoxycarbonyl)benzophenone (2.40 g, 10 mmol) in pentane (40 ml)and CH₂Cl₂ (90 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 10% ether in hexanes) to afford trioxolane OZ138 (1.00 g,25%) as a colorless solid. mp 144-146° C. (ether); ¹H NMR (500 MHz,CDCl₃) δ 1.60-2.29 (m, 14H), 3.91 (s, 3H), 7.31-7.39 (m, 3H), 7.43-7.52(m, 2H), 7.63 (d, J=8.3 Hz, 2H), 8.03 (d, J=8.5 Hz, 2H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.58, 26.99, 33.32, 34.86, 34.88, 35.31, 36.13, 36.31,36.86, 51.99, 109.28, 114.26, 126.76, 126.96, 128.22, 128.97, 129.42,130.37, 138.83, 145.73, 166.69. Anal. Calcd for C₂₅H₂₆O₅: C, 73.87; H,6.45. Found: C, 74.07; H, 6.55.

[0158]cis-Adamantane-2-spiro-3′-8′-[(4′-phenyl-1′-piperazinyl)carbonyl]-1,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ140). A solution of OZ72 (0.31 g, 1.0 mmol), DCC (0.27g, 1.3 mmol), and HOBT (0.16 g, 1.3 mmol) in CHCl₃ (15 ml) was stirredat 0° C. for 15 min before 1-phenylpiperazine (0.21 g, 1.3 mmol) wasadded. The mixture was then warmed to rt, stirred overnight, andconcentrated. The residue was purified by flash chromatography (silicagel, 1% methanol in chloroform) to afford a solid, which was dissolvedin chloroform (20 ml) and filtered. The filtrate was concentrated,redissolved in chloroform (15 ml) and ether (30 ml), and filtered. Thefiltrate was treated with 1 M ethereal HCl (1.5 ml) to afford trioxolaneOZ140 (0.36 g, 74%) as a colorless solid. mp. 155-158° C.(chloroform/ether, 1:2); ¹H NMR (500 MHz, CDCl₃) δ 1.42-2.23 (m, 22H),2.44-2.62 (m, 1H), 3.51 (br s, 4H), 4.28 (br s, 4H), 7.42-7.60 (m, 3H),7.79-7.95 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.59, 26.80, 27.01,33.54, 34.84, 34.89, 36.54, 36.87, 38.53, 39.32, 55.25, 107.61, 111.61,121.22, 130.05, 130.57, 142.36, 173.49. Anal. Calcd for C₂₇H₃₇ClN₂O₄: C,66.31; H, 7.63; N, 5.73. Found: C, 66.26; H, 7.45; N, 5.83.

[0159]cis-Adamantane-2-spiro-3′-1′,2′,4′-trioxaspiro[4.5]decane-8′-methylimidazole-1-carboxylate (OZ141). To a solution of OZ119 (0.29 g, 1 mmol)in CH₃CN(10 ml) and THF (3 ml) was added 1,1′-carbonyldiimidazole (0.21g, 1.3 mmol). The mixture was stirred at rt for 2 h before beingquenched with cold water (50 ml). The resulting precipitate wascollected by filtration, washed with water, and dried to affordtrioxolane OZ141 (0.34 g, 91%) as a colorless solid. mp 110-112° C.(water); ¹H NMR (500 MHz, CDCl₃) δ 1.25-1.50 (m, 2H), 1.51-2.21 (m,21H), 4.25 (d, J=6.3 Hz, 2H), 7.07 (s, 1H), 7.42 (s, 1H), 8.13 (s, 1H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.61, 27.02, 33.54, 34.86, 34.88, 35.66,36.57, 36.90, 72.07, 108.17, 111.59, 117.03, 130.76, 137.07, 148.71.Anal. Calcd for C₂₁H₂₈N₂O₅: C, 64.93; H, 7.27; N, 7.21. Found: C, 65.12;H, 7.12; N, 7.25.

[0160]Adamantane-2-spiro-3′-8′-p-tolylaminocarbonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ142). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (101mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added p-tolyl isocyanate (133mg, 1 mmol). The mixture was stirred at rt for 3 h before removal ofsolvents. The residue was triturated with water (10 ml) and filtered.Recrystallization of the solid from 95% ethanol gave trioxolane OZ142(280 mg, 70%) as a colorless solid. mp 150-152° C. (95% ethanol); ¹H NMR(500 MHz, CDCl₃) δ 1.61-2.19 (m, 18H), 2.29 (s, 3H), 3.43-3.71 (m, 4H),6.44 (s, 1H), 7.08 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H); ¹³C NMR(125.7 MHz, CDCl₃) δ 20.65, 26.60, 26.99, 34.46, 34.84, 34.94, 36.58,36.84, 42.46, 106.90, 112.25, 120.44, 129.40, 132.85, 136.53, 155.13.Anal. Calcd for C₂₃H₃₀N₂O₄: C, 69.32; H, 7.59; N, 7.03. Found: C, 69.10;H, 7.50; N, 7.08.

[0161]Adamantane-2-spiro-3′-8′-(t-butylaminocarbonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ143). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (101mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added tert-butyl isocyanate(100 mg, 1 mmol). The mixture was stirred at rt for 6 h before removalof solvents. The residue was triturated with water (10 ml) and filtered.Recrystallization of the solid from 95% ethanol gave trioxolane OZ143(185 mg, 51%) as a colorless solid. mp 142-144° C. (95% ethanol); ¹H NMR(500 MHz, CDCl₃) δ 1.35 (s, 9H), 1.62-2.09 (m, 18H), 3.35-3.59 (m, 4H),4.34 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.60, 27.00, 29.51, 34.38,34.84, 34.93, 36.57, 36.86, 42.22, 50.82, 107.13, 112.08, 156.72. Anal.Calcd for C₂₀H₃₂N₂O₄: C, 65.91; H, 8.85; N, 7.69. Found: C, 66.19; H,8.50; N, 7.62.

[0162]Adamantane-2-spiro-3′-8′-(phenylaminothiocarbonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ144). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (101mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added phenyl isothiocyanate(135 mg, 1 mmol). The mixture was stirred at rt for 6 h before removalof solvents. The residue was triturated with water (10 ml) and filtered.Recrystallization of the solid from 95% ethanol gave trioxolane OZ144(224 mg, 56%) as a colorless solid. mp 136-138° C. (95% ethanol); ¹H NMR(500 MHz, CDCl₃) δ 1.60-2.19 (m, 18H), 3.78-4.05 (m, 4H), 7.07-7.18 (m,3H), 7.32 (s, 1H), 7.28-7.37 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.56, 26.96, 34.09, 34.82, 34.92, 36.52, 36.81, 47.59, 106.54, 112.45,122.59, 125.13, 129.27, 140.42, 184.18. Anal. Calcd for C₂₂H₂₈N₂O₃S: C,65.97; H, 7.05; N, 6.99. Found: C, 65.93; H, 7.15; N, 7.13.

[0163]cis-Adamantane-2-spiro-3′-8′-(1′H-imidazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ145). Step 1. To a solution of OZ119 (0.29 g, 1 mmol) andtriethylamine (0.15 g, 1.5 mmol) in CH₂Cl₂ (5 ml) at 0° C. was addeddropwise a solution of methanesulfonyl chloride (0.14 g, 1.2 mmol) inCH₂Cl₂ (1 ml). The mixture was stirred at rt for 1 h before beingquenched with water (5 ml). After separation of the aqueous layer, theorganic layer was washed with water (5 ml) and brine (5 ml), dried overMgSO₄, filtered, and concentrated to afford the methanesulfonate (0.34g, 92%) as a colorless solid. mp 82-84° C. (75% ethanol); ¹H NMR (500MHz, CDCl₃) δ 1.25-1.34 (m, 2H), 1.66-2.02 (m, 21H), 3.00 (s, 3H), 4.04(d, J=6.3 Hz, 2H). Step 2. To a suspension of 60% NaH (0.08 g, 2 mmol)in DMF (4 ml) under nitrogen at 0° C. was added a solution of imidazole(0.14 g, 2 mmol) in DMF (4 ml). The mixture was stirred for 30 minbefore a solution of the above methanesulfonate (0.34 g, 0.9 mmol) inDMF (4 ml) was added dropwise. The mixture was heated at 50° C. for 2 hbefore being quenched with water (40 ml) and then extracted with ethylacetate (3×30 ml). The combined extracts were washed with brine (3×30ml), dried over MgSO₄, filtered, and concentrated. Crystallization ofthe residue from hexanes/CH₂Cl₂ (4:1) gave trioxolane OZ145 (0.17 g,55%) as a colorless solid. mp 125-128° C. (hexanes/CH₂Cl₂, 4:1); ¹H NMRNMR (500 MHz, CDCl₃) δ 1.17-1.39 (m, 2H), 1.55-2.18 (m, 21H), 3.77 (d,J=7.3 Hz, 2H), 6.86 (s, 1H), 7.05 (s, 1H), 7.42 (s, 1H); ¹³C NM (125.7MHz, CDCl₃) δ 26.59, 26.99, 27.70, 33.58, 34.85, 34.87, 36.53, 36.88,37.97, 52.49, 108.25, 111.60, 119.16, 129.55, 137.43. Anal. Calcd forC₂₀H₂₈N₂O₃.0.2H₂O: C, 69.02; H, 8.22; N, 8.05. Found: C, 68.81; H, 8.11;N, 7.96.

[0164]cis-Adamantane-2-spiro-3′-8′-phthalimidomethyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ146). A solution of O-methyl 2-adamantanone oxime (2.23 g, 12.4 mmol)and 4-phthalimidomethylcyclohexanone (3.20 g, 12.4 mmol) in pentane (100ml) and CH₂Cl₂ (50 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 25% ether in hexanes) to afford trioxolane OZ146 (1.66 g,32%) as a colorless solid. mp 147-150° C. (ethanol); ¹H NMR NMR (500MHz, CDCl₃) δ 1.23-1.44 (m, 2H), 1.45-2.08 (m, 21H), 3.56 (d, J=7.0 Hz,2H), 7.69-7.74 (m, 2H), 7.81-7.89 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.61, 27.01, 27.88, 33.66, 34.85, 34.87, 35.70, 36.51, 36.92, 43.12,108.52, 111.35, 123.22, 132.20, 133.86, 168.47. Anal. Calcd forC₂₅H₂₉NO₅: C, 70.90; H, 6.90; N, 3.31. Found: C, 71.16; H, 6.75; N,3.21.

[0165] Adamantane-2-spiro-3′-1′,2′,4′-trioxaspiro[4.5]decane-8′-ylimidazole-1-carboxylate (OZ147). To a solution of OZ32 (0.28 g, 1 mmol)in CH₃CN (10 ml) and THF (3 ml) was added 1,1′-carbonyldiimidazole (0.21g, 1.3 mmol). The mixture was stirred at 60-70° C. for 2 h before beingcooled to rt and diluted with cold water (50 ml). The resultingprecipitate was collected by filtration, washed with water, and dried toafford trioxolane OZ147 (0.32 g, 90%, 1:1 mixture of two diastereomers)as a colorless solid. mp 116-118° C. (water); ¹H NMR (500 MHz, CDCl₃) δ1.62-2.21 (m, 22H), 5.05-5.22 (m, 1H), 7.07 (s, 0.5H), 7.08 (s, 0.5H),7.41 (s, 0.5H), 7.43 (s, 0.5H), 8.13 (s, 0.5H), 8.15 (s, 0.5H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.58, 27.00, 28.05, 28.32, 30.53, 30.88, 34.83,34.94, 36.48, 36.56, 36.85, 74.61, 75.01, 107.24, 107.30, 112.01,112.11, 117.01, 117.04, 130.74, 137.08, 148.09, 148.14. Anal. Calcd forC₂₀H₂₆N₂O₅: C, 64.15; H, 7.00; N, 7.48. Found: C, 64.22; H, 7.00; N,7.30.

[0166]cis-Adamantane-2-spiro-3′-1′,2′,4′-trioxaspiro[4.5]decane-8′-methyl4-phenylpiperazine-1-carboxylate (OZ148). To a solution of OZ141 (310mg, 0.86 mmol) in THF (10 ml) at 0° C. was added methyl triflate (142mg, 0.86 mmol). The mixture was stirred at 0° C. for 30 min before1-phenylpiperazine (140 mg, 0.86 mmol) was added. The reaction wasstirred at rt for 18 h before removal of solvents. Crystallization ofthe residue from ethanol/water (3:1) gave trioxolane OZ148 (323 mg, 83%)as a colorless solid. mp 145-146° C. (ethanol/water, 3:1); ¹H NMR (500MHz, CDCl₃) δ 1.21-1.42 (m, 2H), 1.58-2.10 (m, 21H), 3.15 (br s, 4H),3.63 (br s, 4H), 3.96 (d, J=6.2 Hz, 2H), 6.90 (dd, J=7.5, 7.5 Hz, 1H),6.93 (d, J=7.8 Hz, 2H), 7.28 (dd, J=8.6, 7.4 Hz, 2H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.61, 26.79, 27.01, 33.77, 34.87, 34.88, 36.03, 36.55,36.91, 43.81, 49.46, 69.57, 108.61, 111.39, 116.71, 120.40, 129.20,151.27,155.45. Anal. Calcd for C₂₈H₃₈N₂O₅: C, 69.68; H, 7.94; N, 5.80.Found: C, 69.83; H, 7.98; N, 5.86.

[0167]Adamantane-2-spiro-3′-1′,2′,4′-trioxaspiro[4.5]decane-8′-spiro-1″-3″-oxo-3″H-isobenzofuran(OZ149). A solution of O-methyl 2-adamantanone oxime (0.54 g, 3 mmol)and spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′,4-dione (0.65 g, 3mmol) in pentane (50 ml) and CH₂Cl₂ (50 ml) was treated with ozoneaccording to the general procedure. The crude product was purified byflash chromatography (silica gel, 25% ether in hexanes) to affordtrioxolane OZ149 (0.50 g, 44%) as a colorless solid. mp 160-162° C.(ethanol/water, 3:1); ¹H NMR NMR (500 MHz, CDCl₃) δ 1.65-2.12 (m, 18H),2.21 (ddd, J=13.8, 13.8, 3.9 Hz, 2H), 2.31 (ddd, J=13.7, 13.7, 4.0 Hz,2H), 7.38 (d, J=7.5 Hz, 1H), 7.52 (dd, J=7.5, 7.5 Hz, 1H), 7.67 (dd,J=7.5, 7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.61, 26.97, 30.73, 34.27, 34.85, 34.88, 36.60, 36.86, 84.97, 107.56,112.05, 120.85, 124.64, 125.96,129.25, 134.08, 153.70, 169.43. Anal.Calcd for C₂₃H₂₆O₅: C, 72.23; H, 6.85. Found: C, 72.12; H, 6.65.

[0168]Adamantane-2-spiro-3′-8′-(4′-nitrophenyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ151). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (101mg, 1 mmol) in CH₃CN (10 ml) was added 4-nitrophenyl triflate (271 mg, 1mmol). The mixture was stirred at 65° C. for 64 h before removal ofsolvents. The crude product was purified by flash chromatography (silicagel, 5% ether in hexanes) and by subsequent crystallization frommethanol to afford trioxolane OZ151 (120 mg, 31%) as a yellowish solid.mp 140-142° C. (methanol); ¹H NMR (500 MHz, CDCl₃) δ 1.61-2.19 (m, 18H),3.48-3.75 (m, 4H), 6.83 (d, J=9.3 Hz, 2H), 8.11 (d, J=9.3 Hz, 2H); ¹³CNMR (125.7 MHz, CDCl₃).26.54, 26.94, 33.84, 34.82, 34.92, 36.55, 36.79,45.57, 106.63, 112.40, 112.93, 126.05, 138.63, 154.14. Anal. Calcd forC₂₁H₂₆N₂O₅: C, 65.27; H, 6.78; N, 7.25. Found: C, 65.40; H, 6.66; N,7.29.

[0169]5-Hydroxyadamantane-2-spiro-3′-1′,2′,4′,9′,12′-pentaoxadispiro[4.2.4.2]tetradecane(OZ152). Step 1. A solution of O-methyl 5-acetoxy-2-adamantanone oxime(1.18 g, 5.0 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (790 mg, 5.0 mmol)in pentane (20 ml) and CH₂Cl₂ (100 ml) was treated with ozone accordingto the general procedure. The crude product was purified by flashchromatography (silica gel, 30% ether in petroleum ether) to afford5-acetoxyadamantane-2-spiro-3′-1′,2′,4′,9′,12′-pentaoxadispiro[4.2.4.2]tetradecane(0.61 g, 32%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 1.78-2.28(m, 24H), 3.95 (s, 4H). Step 2. A mixture of the above acetatetrioxolane (1.30 g, 3.42 mmol), EtOH (7 ml), and 30% aq. KOH (6 ml) washeated at 50° C. for 2 h. After removal of the solvent, the residue wasdiluted with water and extracted with ether. The organic layer waswashed with water and brine, dried over MgSO₄, and concentrated. Thecrude product was purified by flash chromatography (silica gel, 80%ether in hexanes) to afford trioxolane OZ152 (100 mg, 9%, minor isomer,eluted first) as a colorless solid and trioxolane OZ153 (414 mg, 36%,major isomer, eluted second) as a colorless solid. For OZ152: mp132-134° C. (ether); ¹H NMR (500 MHz, CDCl₃) δ 1.56-2.19 (m, 21H), 3.95(s, 4H); ¹³C NMR (125.7 MHz, CDCl₃).29.27, 31.65, 32.11, 33.52, 38.10,42.13, 44.59, 64.39, 67.01, 107.84, 108.47, 110.40. Anal. Calcd forC₁₈H₂₆O₆: C, 63.89; H, 7.74. Found: C, 64.02; H, 7.81.

[0170]5-Hydroxyadamantane-2-spiro-3′-1′,2′,4′,9′,12′-pentaoxadispiro[4.2.4.2]tetradecane(OZ153). For preparation, see OZ152. mp 112-114° C. (ether); ¹H NMR (500MHz, CDCl₃) δ 1.54-2.22 (m, 21H), 3.98 (s, 4H); ¹³C NMR (125.7 MHz,CDCl₃) δ 28.85, 31.72, 32.09, 33.40, 38.31, 42.11, 44.54, 64.36, 67.37,107.80, 108.50, 110.36. Anal. Calcd for C₁₈H₂₆O₆: C, 63.89; H, 7.74.Found: C, 64.03; H, 7.66.

[0171]cis-Adamantane-2-spiro-3′-8′-[4′-(4′,5′-dihydro-4′,4′-dimethyl-2′-oxazolyl)phenyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ154). A solution of O-methyl 2-adamantanone oxime (1.32 g, 7.4 mmol)and 4-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]cyclohexanone (2.00g, 7.4 mmol) in pentane (100 ml) and CH₂Cl₂ (50 ml) was treated withozone according to the general procedure. The crude product was purifiedby flash chromatography (silica gel, 10 to 30% ether in hexanes) toafford trioxolane OZ154 (0.80 g, 25%) as a colorless solid. mp 138-140°C. (ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.37 (s, 6H), 1.59-2.16 (m,22H), 2.51-2.68 (m, 1H), 4.08 (s, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.85 (d,J=8.0 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.63, 27.03, 28.38, 31.29,34.70, 34.88, 34.90, 36.56, 36.93, 42.98, 67.52, 79.15, 108.26, 111.46,126.22, 126.70, 128.44,149.58, 162.01. Anal. Calcd for C₂₇H₃₅NO₄: C,74.11; H, 8.06; N, 3.20. Found: C, 74.35; H, 8.08; N, 3.18.

[0172]cis-Adamantane-2-spiro-3′-8′-[[(2′-hydroxyethyl)amino]carbonyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ155). A solution of OZ72 (0.31 g, 1.0 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.29 g,1.5 mmol), HOBT (0.20 g, 1.5 mmol), and 2-aminoethanol (0.09 g, 1.5mmol) in DMF (10 ml) was stirred at rt for 18h before being quenchedwith 2 M aq. HCl (30 ml). The mixture was extracted with ethyl acetate(4×30 ml), and the combined extracts were washed with water (2×30 ml)and brine (30 ml), dried over MgSO₄, and concentrated. The residue waspurified by flash chromatography (silica gel, 5% methanol in CH₂Cl₂) toafford trioxolane OZ155 (0.16 g, 46%) as a colorless solid. mp 114-116°C. (ether/CH₂Cl₂ 2:1); ¹H NMR (500 MHz, CDCl₃) δ 1.59-2.08 (m, 22H),2.17 (br s, 1H), 3.38-3.45 (m, 2H), 3.71 (t, J=4.8 Hz, 2H), 6.13 (s,1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44, 26.84, 26.99, 33.58, 34.75,34.78, 36.35, 36.75, 42.27, 43.58, 62.31, 107.77, 111.53, 176.04. Anal.Calcd for C₁₉H₂₉NO₅: C, 64.93; H, 8.32; N, 3.99. Found: C, 64.68; H,8.11; N, 3.93.

[0173]cis-Adamantane-2-spiro-3′-8′-benzyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ156). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol)and 4-benzylcyclohexanone (940 mg, 5 mmol) in cyclohexane (80 ml) andCH₂Cl₂ (20 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 5% ether in hexanes) and by subsequent recrystallizationfrom ethanol/CH₂Cl₂ (19:1) to afford trioxolane OZ156 (825 mg, 47%) as acolorless solid. mp 87-89° C. (ethanol/CH₂Cl₂, 19:1); ¹H NMR (500 MHz,CDCl₃) δ 1.18-1.37 (m, 2H), 1.49-2.20 (m, 21H), 2.50 (d, J=7.2 Hz, 2H),7.09-7.40 (m, 5H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.49, 26.88, 29.93,34.15, 34.78, 34.79, 36.39, 36.81, 38.16, 42.89, 108.94, 111.19, 125.78,128.16, 129.07, 140.86. Anal. Calcd for C₂₃H₃₀O₅: C, 77.93; H, 8.53.Found: C, 78.17; H, 8.45.

[0174]Adamantane-2-spiro-3′-8′-[(4′-methyl-1′-piperazinyl)carbonyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ157). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (404mg, 4 mmol) in CH₂Cl₂ (7 ml) at 0° C. was added4-methyl-1-piperazinecarbonyl chloride hydrochloride (220 mg, 1.1 mmol).The mixture was stirred at rt for 16 h, diluted with CH₂Cl₂ (10 ml),washed with water (2×10 ml) and brine (10 ml), dried over MgSO₄, andconcentrated. Crystallization of the residue from ethanol gavetrioxolane OZ157 (105 mg, 27%) as a colorless solid. mp 146-148° C.(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.61-2.09 (m, 18H), 2.30 (s, 3H),2.31-2.48 (m, 4H), 3.21-3.47 (m, 8H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.61, 27.01, 34.52, 34.85, 34.95, 36.59, 36.87, 44.77, 46.14, 46.87,54.91, 107.24, 112.04, 163.68. Anal. Calcd for C₂₁H₃₃N₃O₄: C, 64.42; H,8.50; N, 10.73. Found: C, 64.34; H, 8.37; N, 10.61.

[0175]Adamantane-2-spiro-3′-8′-(1′-piperidinyl)-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ159). To a solution of OZ05 (555 mg, 2 mmol) in1,2-dichloroethane (10 ml) were added piperidine (187 mg, 2.2 mmol) andacetic acid (10 drops). The reaction mixture was stirred at rt for 15min before sodium triacetoxyborohydride (677 mg, 3.2 mmol) was added.The mixture was stirred for 5 h before being quenched with 1 M aq. NaOH(2 ml). The resulting mixture was extracted with CH₂Cl₂ (40 ml), washedwith water (2×10 ml) and brine (2×10 ml), dried over MgSO₄, andconcentrated. The residue was dissolved in ether (2 ml), treated withexcess 2 M ethereal HCl, and filtered to give trioxolane OZ159 (460 mg,60%, 1:1 mixture of two diastereomers) as a colorless solid. mp 12° C.dec (ether); ¹H NMR (500 MHz, CDCl₃) δ 1.39 (br s, 1H), 1.58-2.20 (m,23H), 2.21-2.60 (m, 4H), 2.78 (br s, 2H), 3.11 (br s, 1H), 3.28-3.59 (m,2H), 11.94 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 22.53, 22.69, 22.73,23.33, 23.43, 26.37, 26.40, 26.78, 32.65, 32.81, 34.66, 34.69, 34.72,34.91, 36.28, 36.64, 49.77, 49.98, 63.81, 64.20, 106.50, 106.56, 112.20,112.37. Anal. Calcd for C₂₁H₃₄ClNO₃.0.25H₂O: C, 64.93; H, 8.95; N, 3.61.Found: C, 64.48; H, 8.59; N, 3.63.

[0176]Adamantane-2-spiro-3′-8′-(benzylamino)-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ160). To a solution of OZ05 (555 mg, 2 mmol) in1,2-dichloroethane (10 ml) were added benzylamine (236 mg, 2.2 mmol) andacetic acid (10 drops). The reaction mixture was stirred at rt for 15min before sodium triacetoxyborohydride (677 mg, 3.2 mmol) was added.The mixture was stirred for 5 h before being quenched with 1 M aq. NaOH(2 ml). The resulting mixture was extracted with CH₂Cl₂ (40 ml), washedwith water (2×10 ml) and brine (2×10 ml), dried over MgSO₄, andconcentrated. The residue was dissolved in ether (2 ml), treated withexcess 2 M ethereal HCl, and filtered to give trioxolane OZ160 (567 mg,70%, 2:1 mixture of two diastereomers) as a colorless solid. mp 160° C.dec (ether); ¹H NMR (500 MHz, CDCl₃) δ 1.42-2.31 (m, 22H), 2.78-2.89 (m,1H), 3.914.19 (m, 2H), 7.31-7.46 (m, 3H), 7.59-7.71 (m, 2H), 10.00 (brs, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 25.95, 26.53, 26.89, 32.21, 34.78,34.92, 36.38, 36.45, 36.81, 47.82, 53.65, 106.71, 106.79, 111.72,112.33, 129.07, 129.12, 129.30, 129.35, 130.25, 130.51, 130.57. Anal.Calcd for C₂₃H₃₂ClNO₃: C, 68.05; H, 7.95; N, 3.45. Found: C, 67.89; H,7.71; N, 3.35.

[0177]Adamantane-2-spiro-3′-8′-[[3′-(4′-morpholinyl)propyl]amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ161). To a solution of OZ05 (555 mg, 2 mmol) in 1,2-dichloroethane(10 ml) were added 4-(3-aminopropyl)morpholine (317 mg, 2.2 mmol) andacetic acid (10 drops). The reaction mixture was stirred at rt for 15min before sodium triacetoxyborohydride (677 mg, 3.2 mmol) was added.The mixture was stirred for 5 h before being quenched with 1 M aq. NaOH(2 ml). The resulting mixture was extracted with CH₂Cl₂ (40 ml), washedwith water (2×10 ml) and brine (2×10 ml), dried over MgSO₄, andconcentrated. The residue was dissolved in ether (2 ml), treated withexcess 2 M ethereal HCl, and filtered to give trioxolane OZ161 (552 mg,68%, 1:1 mixture of two diastereomers) as a colorless solid. mp 70-72°C. (ether); ¹H NMR (500 MHz, CDCl₃) δ 1.31-2.20 (m, 24H), 2.32-2.60 (m,7H), 2.61-2.78 (m, 2H), 3.62-3.83 (m, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.29, 26.70, 26.77, 26.81, 29.61, 30.02, 31.97, 32.42, 34.55, 34.59,34.63, 34.70, 36.16, 36.20, 36.61, 43.27, 45.76, 46.00, 53.62, 53.64,54.62, 54.86, 57.31, 57.42, 66.80, 108.35, 108.39, 111.05, 111.34. Anal.Calcd for C₂₃H₃₈N₂O₄: C, 67.95; H, 9.42; N, 6.89. Found: C, 67.84; H,9.30; N, 6.68.

[0178]Adamantane-2-spiro-3′-8′-(cyclohexylamino)-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ162). To a solution of OZ05 (555 mg, 2 mmol) in1,2-dichloroethane (10 ml) were added cyclohexylamine (218 mg, 2.2 mmol)and acetic acid (10 drops). The reaction mixture was stirred at rt for15 min before sodium triacetoxyborohydride (677 mg, 3.2 mmol) was added.The mixture was stirred for 5 h before being quenched with 1 M aq. NaOH(2 ml). The resulting mixture was extracted with CH₂Cl₂ (40 ml), washedwith water (2×10 ml) and brine (2×10 ml), dried over MgSO₄, andconcentrated. The residue was dissolved in ether (2 ml), treated withexcess 2 M ethereal HCl, and filtered to give OZ162 (516 mg, 65%, 1:1mixture of two diastereomers) as a colorless solid. mp 240° C. dec(ether); ¹H NMR (500 MHz, CDCl₃) δ 1.26 (br s, 2H), 1.55-2.42 (m, 30H),2.97-3.21 (m, 2H), 9.33 (br s, 1H), 9.37 (br s, 1H); ¹³C NMR (125.7 MHz,CDCl₃) δ 24.83, 24.87, 26.56, 26.90, 26.97, 29.45, 32.58, 34.80, 34.82,34.94, 36.39, 36.51, 36.85, 52.70, 54.89, 55.12, 106.82, 106.91, 111.67,112.32. Anal. Calcd for C₂₂H₃₆ClNO₃: C, 66.39; H, 9.12; N, 3.52. Found:C, 66.28; H, 8.97; N, 3.54.

[0179]cis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ163). A solution of OZ146 (423 mg, 1 mmol) andhydrazine monohydrate (150 mg, 3 mmol) in chloroform (9 ml) and methanol(1 ml) was heated at 55° C. for 48 h. The reaction mixture was cooled tort and filtered to remove solid by-products. The filtrate was washedwith water (10 ml) and brine (10 ml), dried over MgSO₄, filtered, andconcentrated. The solid was dissolved in ether (10 ml), treated with 1 Methereal HCl (1.2 ml), and filtered. Recrystallization from ether gavetrioxolane OZ163 (80 mg, 24%) as a yellowish solid. mp 146° C. dec(ether); ¹H NMR (500 MHz, CDCl₃) δ 1.23-1.42 (m, 2H), 1.59-2.20 (m,21H), 2.86 (br s, 2H), 8.35 (br s, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.45, 26.86, 27.61, 33.27, 34.45, 34.76, 36.37, 36.77, 39.25, 44.88,107.92, 111.52. Anal. Calcd for C₁₇H₂₈ClNO₃: C, 61.90; H, 8.56; N, 4.25.Found: C, 59.83; H, 8.21; N, 5.07.

[0180]cis-Adamantane-2-spiro-3′-8′-[4′-(ethoxycarbonyl)phenyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ164). A solution of O-methyl 2-adamantanone oxime (1.10 g, 6.2 mmol)and 4-[4-(ethoxycarbonyl)phenyl]cyclohexanone (1.70 g, 6.2 mmol) inpentane (100 ml) and CH₂Cl₂ (50 ml) was treated with ozone according tothe general procedure. The crude product was purified by flashchromatography (silica gel, 10% ether in hexanes) to afford trioxolaneOZ164 (1.60 g, 63%) as a colorless solid. mp 129-132° C. (hexanes/ether9:1); ¹H NMR (500 MHz, CDCl₃) δ 1.38 (t, J=7.2 Hz, 3H), 1.63-2.22 (m,22H), 2.56-2.71 (m, 1H), 4.36 (q, J=7.2 Hz, 2H), 7.27 (d, J=7.8 Hz, 2H),7.96 (d, J=8.0 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 14.34, 26.49,26.89, 31.18, 34.59, 34.80, 36.42, 36.80, 42.99, 60.76, 108.18, 111.51,126.77, 128.54, 129.74, 151.39, 166.57. Anal. Calcd for C₂₅H₃₂O₅: C,72.79; H, 7.82. Found: C, 72.83; H, 7.90.

[0181]cis-Adamantane-2-spiro-3′-8′-(4′-carboxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ165). A mixture of OZ164 (1.38 g, 3.35 mmol), KOH (1.13 g), THF (30ml), methanol (30 ml), and water (6 ml) was heated at 50° C. for 2 h.The mixture was concentrated to 10 ml, diluted with water (50 ml), andextracted with ethyl acetate. The aqueous layer was acidified with 1 Maq. HCl to pH=2, and the resulting solid was collected by filtration togive trioxolane OZ165 (1.08 g, 84%) as a colorless solid. mp 157° C.dec; ¹H NMR (500 MHz, CDCl₃) δ 1.63-2.22 (m, 22H), 2.57-2.72 (m, 1H),7.31 (d, J=8.3 Hz, 2H), 8.03 (d, J=8.1 Hz, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.49, 26.90, 31.14, 34.58, 34.81, 36.43, 36.80, 43.10, 108.14,111.54, 126.99, 127.23, 130.46, 152.54, 171.45. Anal. Calcd forC₂₃H₂₈O₅: C, 71.85; H, 7.34. Found: C, 71.68; H, 7.33.

[0182]cis-Adamantane-2-spiro-3′-8′-[[4′-(ethoxycarbonyl)phenoxy]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ166). To a solution of OZ119 (0.59 g, 2.0 mmol), triphenylphosphine(0.63 g, 2.4 mmol), and ethyl 4-hydroxybenzoate (0.50 g, 3.0 mmol) inTHF (12 ml) at 0° C. was added dropwise a solution of diisopropylazodicarboxylate (0.65 g, 3.2 mmol) in THF (0.5 ml). The mixture wasthen warmed to rt and stirred at rt for 2 h before removal of solvents.The crude product was purified by flash chromatography (silica gel, 20%ether in hexanes) to afford trioxolane OZ166 (0.65 g, 73%) as acolorless solid. mp 142-143° C. (hexanes/ether 9:1); ¹H NMR (500 MHz,CDCl₃) δ 1.38 (t, J=7.2 Hz, 3H), 1.30-1.58 (m, 2H), 1.60-2.21 (m, 21H),3.82 (d, J=5.9 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H),7.97 (d, J=8.8 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 14.35, 26.48,26.85, 26.87, 33.72, 34.78, 34.80, 36.14, 36.40, 36.79, 60.58, 72.43,108.64, 111.41, 113.97, 122.84, 131.50, 162.75, 166.38. Anal. Calcd forC₂₆H₃₄O₆: C, 70.56; H, 7.74. Found: C, 70.72; H, 7.76.

[0183]trans-Adamantane-2-spiro-3′-8′-phthalimidomethyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ167). For the major isomer (cis), see OZ146. A solution of O-methyl2-adamantanone oxime (2.23 g, 12.4 mmol) and4-phthalimidomethylcyclohexanone (3.20 g, 12.4 mmol) in pentane (100 ml)and CH₂Cl₂ (50 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 25% ether in hexanes and 40% CH₂Cl₂ in hexanes) to affordtrioxolane OZ167 (0.16 g, 3%) as a colorless solid. mp 140-142° C.(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.40-2.17 (m, 23H), 3.60 (d, J=7.5Hz, 2H), 7.68-7.75 (m, 2H), 7.82-7.88 (m, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.63, 27.03, 27.69, 33.46, 34.83, 34.99, 35.71, 36.51, 36.93,42.98, 108.58, 111.74, 123.25, 132.19, 133.91, 168.52. Anal. Calcd forC₂₅H₂₉NO₅: C, 70.90; H, 6.90; N, 3.31. Found: C, 70.75; H, 7.03; N,3.25.

[0184]Adamantane-2-spiro-3′-1′,2′,4′,9′,10′,12′-hexaoxadispiro[4.2.4.2]tetradecane-11′-spiro-2″-adamantane(OZ169). A solution of O-methyl 2-adamantanone oxime (1.80 g, 10 mmol)and 1,4-cyclohexanedione (2.24 g, 20 mmol) in pentane (60 ml) and CH₂Cl₂(40 ml) was treated with ozone according to the general procedure. Thecrude product was purified by flash chromatography (silica gel, 10%ether in hexanes) to afford trioxolane OZ169 (346 mg, 16%, 2:1 mixtureof two diastereomers) as a colorless solid. mp 156-158° C. (hexanes); ¹HNMR (500 MHz, CDCl₃) δ 1.92 (s, 8H), 1.60-2.25 (m, 28H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.45, 26.83, 26.86, 31.57, 34.72, 34.75, 34.80, 34.84,36.29, 36.31, 36.74, 107.65, 107.71, 111.72. Anal. Calcd for C₂₆H₃₆O₆:C, 70.24; H, 8.16. Found: C, 70.18; H, 8.28.

[0185]Adamantane-2-spiro-3′-8′-[(2′,2′,6′,6′-tetramethyl-4′-piperidinyl)amino]-1′,2′,4′-trioxaspiro[4.5]decanedihydrochloride (OZ171). To a solution of OZ05 (555 mg, 2 mmol) in1,2-dichloroethane (10 ml) were added4-amino-2,2,6,6-tetramethylpiperidine (344 mg, 2.2 mmol) and acetic acid(10 drops). The reaction mixture was stirred at rt for 15 min beforesodium triacetoxyborohydride (677 mg, 3.2 mmol) was added. The mixturewas stirred for 5 h before being quenched with 1 M aq. NaOH (2 ml). Theresulting mixture was extracted with CH₂Cl₂ (40 ml), washed with water(2×10 ml) and brine (2×10 ml), dried over MgSO₄, and concentrated. Theresidue was dissolved in ether (2 ml), treated with excess 2 M etherealHCl, and filtered to give trioxolane OZ171 (650 mg, 66%, 1:1 mixture oftwo diastereomers) as a colorless solid. mp 165° C. dec (ether); ¹H NMR(500 MHz, DMSO-d₆) δ 1.43 (s, 6H), 1.45 (s, 6H), 1.46-2.37 (m, 26H),3.14-3.40 (m, 1H), 3.55-3.79 (m, 1H), 8.28-8.45 (m, 1H), 9.25-9.47 (m,2H), 9.55-9.72 (m, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 24.03, 24.07,25.96, 26.38, 29.78, 31.70, 34.38, 34.43, 34.55, 35.81, 35.88, 36.22,37.00, 45.66, 45.71, 50.74, 50.93, 56.22, 56.26, 107.42, 107.46, 111.13,111.41. Anal. Calcd for C₂₅H₄₄Cl₂N₂O₃.1.5H₂O: C, 57.90; H, 9.14; N,5.40. Found: C, 57.65; H, 8.74; N, 5.36.

[0186] Adamantane-2-spiro-3′-8′-oxo-1′,2′,4′-trioxaspiro[4.5]decaneamidinohydrazone hydrochloride (OZ172). To a solution of OZ05 (555 mg, 2mmol) in THF (11 ml), water (3 ml), and ethanol (3.5 ml) were added 2 Maq. HCl (1.5 ml) and aminoguanidine bicarbonate (299 mg, 2.2 mmol). Themixture was stirred at rt for 30 h before removal of solvents. Theresidue was triturated with ethanol (10 ml) and the resultingprecipitate was collected by filtration and washed with THF to givetrioxolane OZ172 (476 mg, 64%) as a colorless solid. mp 150° C. dec(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.46-2.27 (m, 18H), 2.42-2.61 (m,2H), 2.62-2.83 (m, 2H), 6.34 (s, 1H), 7.63 (br s, 2H), 7.91 (s, 1H),10.95 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃).24.83, 26.37, 26.77, 31.72,32.49, 33.62, 34.70, 34.74, 34.84, 36.23, 36.26, 36.65, 107.26, 112.27,156.57, 157.93. Anal. Calcd for C₁₇H₂₇ClN₄O₃: C, 55.05; H, 7.34; N,15.11. Found: C, 55.14; H, 7.51; N, 15.30.

[0187]Adamantane-2-spiro-3′-8′-[(methoxyacetyl)benzylamino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ173). To a solution of OZ160 (342 mg, 0.84 mmol) in CH₂Cl₂ (10 ml) at0° C. were added triethylamine (255 mg, 2.53 mmol) and methoxyacetylchloride (137 mg, 1.26 mmol). The resulting mixture was stirred at rtfor 16 h, diluted with CH₂Cl₂ (10 ml), and washed with water (10 ml) andbrine (10 ml). The organic layer was separated, dried over MgSO₄, andconcentrated. The residue was triturated with ether to give trioxolaneOZ173 (110 mg, 30%, 3:2 mixture of two diastereomers) as a colorlesssolid. mp 132-134° C. (ether); ¹H NMR (500 MHz, CDCl₃), 1.47-2.20 (m,22H), 3.38 (s, 1.8H), 3.48 (s, 1.2H), 3.99 (s, 1.2H), 4.23 (s, 0.8H),4.46 (s, 1.2H), 4.55 (s, 0.8H), 4.42-4.58 (m, 1H), 7.09-7.46 (m, 5H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.41, 26.80, 26.87, 27.11, 28.74, 33.31,33.54, 34.67, 34.74, 34.93, 36.29, 36.72, 44.76, 45.52, 51.71, 55.36,59.20, 71.54, 72.30, 107.56, 111.65, 125.61, 126.74, 127.10, 127.30,128.33, 128.78, 137.93, 139.04, 169.30, 169.82. Anal. Calcd forC₂₆H₃₅NO₅: C, 70.72; H, 7.99; N, 3.17. Found: C, 70.76; H, 8.02; N,3.08.

[0188]Adamantane-2-spiro-3′-8′-[(methoxyacetyl)cyclohexylamino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ174). To a solution of OZ162 (330 mg, 0.83 mmol) in CH₂Cl₂ (10 ml) at0° C. were added triethylamine (251 mg, 2.49 mmol) and methoxyacetylchloride (135 mg, 1.24 mmol). The resulting mixture was stirred at rtfor 16 h, diluted with CH₂Cl₂ (10 ml), and washed with water (10 ml) andbrine (10 ml). The organic layer was separated, dried over MgSO₄, andconcentrated. The residue was triturated with ether to give trioxolaneOZ174 (109 mg, 30%, 4:1 mixture of two diastereomers) as a colorlesssolid. mp 140-142° C. (ether); ¹H NMR (500 MHz, CDCl₃) δ 1.02-2.20 (m,30H), 2.32-2.72 (m, 2H), 2.81-3.05 (m, 1H), 3.40 (s, 2.4H), 3.42 (s,0.6H), 3.48-3.69 (m, 1H), 4.02 (s, 1.6H), 4.03 (m, 0.4H); ¹³C NMR (125.7MHz, CDCl₃) δ 25.25, 26.00, 26.44, 26.84, 27.89, 29.77, 33.50, 34.21,34.77, 36.32, 36.73, 55.51, 56.10, 58.84, 73.12, 73.71, 107.39, 107.52,111.83, 168.17. Anal. Calcd for C₂₅H₃₉NO₅: C, 69.25; H, 9.07; N, 3.23.Found: C, 69.12; H, 9.06; N, 3.23.

[0189]cis-Adamantane-2-spiro-3′-8′-(2′-hydroxyamino-2′-oxoethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ175). To a solution of OZ78 (322 mg, 1.0 mmol) in ether (10 ml) at 0°C. were added triethylamine (202 mg, 2 mmol) and ethyl chloroformate(217 mg, 2 mmol). The mixture was stirred at 0° C. for 15 min before afreshly prepared solution of hydroxylamine was added. [A suspension ofhydroxylamine hydrochloride (170 mg, 2.48 mmol) and sodium bicarbonate(203 mg, 2.48 mmol) in methanol (5 ml) was stirred at rt for 15 min. Thesupernatant was used as such.] The resulting mixture was stirred at rtfor 12 h, diluted with ether (10 ml), washed with water (10 ml), driedover MgSO₄, and concentrated. The crude product was purified by flashchromatography (silica gel, 5% methanol in CH₂Cl₂) and by subsequentrecrystallization from ethanol to afford trioxolane OZ175 (95 mg, 28%)as a colorless solid. mp 138-140° C. (ethanol); ¹H NMR (500 MHz,DMSO-d₆) δ 0.81-1.27 (m, 3H), 1.40-2.19 (m, 22H), 8.65 (s, 1H), 10.33(s, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.84, 26.25, 29.40, 32.60,33.35, 34.26, 35.81, 36.13, 38.68, 108.33, 110.44, 167.91. Anal. Calcdfor C₁₈H₂₇NO₅: C, 64.07; H, 8.07; N, 4.15. Found: C, 64.11; H, 8.10; N,3.97.

[0190]cis-Adamantane-2-spiro-3′-8′-[(4′-carboxyphenoxy)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ176). A mixture of OZ166 (0.30 g, 0.68 mmol), KOH (0.38 g), THF (10ml), methanol (10 ml), and water (2 ml) was heated at 50° C. for 3 h.The mixture was concentrated to 5 ml, diluted with water (15 ml), andacidified with 1 M aq. HCl (1 ml). The resulting solid was collected byfiltration to give trioxolane OZ176 (0.21 g, 75%) as a colorless solid.mp 165-168° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 1.15-1.27 (m, 2H), 1.50-2.17(m, 21H), 3.88 (d, J=6.2 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.3Hz, 2H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.99, 26.40, 26.53, 33.27,34.45, 35.35, 35.95, 36.26, 72.09, 108.70, 110.71, 114.41, 123.04,131.50, 162.47, 167.15. Anal. Calcd for C₂₄H₃₀O₆: C, 69.54; H, 7.30.Found: C, 69.67; H, 7.21.

[0191]cis-Adamantane-2-spiro-3′-8′-(1′H-1′,2′,4′-triazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ177). To a suspension of 60% NaH (0.08 g, 2 mmol) in DMF (4 ml) undernitrogen at 0° C. was added a solution of 1,2,4-triazole (0.14 g, 2mmol) in DMF (4 ml). The mixture was stirred for 30 min before asolution of the methanesulfonate of OZ119 (0.37 g, 1.0 mmol) in DMF (4ml) was added dropwise. The mixture was heated at 50° C. for 2 h beforebeing quenched with water (40 ml) and then extracted with ethyl acetate(3×30 ml). The combined extracts were washed with brine (3×30 ml), driedover MgSO₄, filtered, and concentrated. Crystallization of the residuefrom hexanes/ether (4:1) gave trioxolane OZ177 (0.21 g, 61%) as acolorless solid. mp 123-124° C. (hexanes/ether 4:1); ¹H NMR (500 MHz,CDCl₃) δ 1.17-1.42 (m, 2H), 1.50-2.19 (m, 21H), 4.02 (d, J=7.0 Hz, 2H),7.95 (s, 1H), 8.02 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.43, 26.82,27.48, 33.43, 34.75, 36.35, 36.47, 36.73, 54.84, 108.19, 111.57, 143.35,152.10. Anal. Calcd for C₁₉H₂₇N₃O₃: C, 66.06; H, 7.88; N, 12.16. Found:C, 65.86; H, 8.06; N, 11.89.

[0192]cis-Adamantane-2-spiro-3′-8′-[(4′-methylsulfonyl)phenyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ178). A solution of O-methyl 2-adamantanone oxime (0.54 g, 3 mmol)and 4-[4-(methylsulfonyl)phenyl]cyclohexanone (0.75 g, 3 mmol) inpentane (50 ml) and CH₂Cl₂ (50 ml) was treated with ozone according tothe general procedure. The crude product was purified by flashchromatography (silica gel, 30% ethyl acetate in hexanes) to affordtrioxolane OZ178 (0.22 g, 18%) as a colorless solid. mp 132-135° C.(hexanes/CH₂Cl₂ 4:1); ¹H NMR (500 MHz, CDCl₃) δ 1.62-2.19 (m, 22H),2.60-2.74 (m, 1H), 3.04 (s, 3H), 7.40 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.0Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.48, 26.88, 31.14, 34.48, 34.80,36.43, 36.78, 42.94, 44.53, 107.95, 111.64, 127.59, 127.80, 138.45,152.59. Anal. Calcd for C₂₃H₃₀O₅S: C, 66.00; H, 7.22. Found: C, 66.08;H, 7.16.

[0193]cis-Adamantane-2-spiro-3′-8′-(1′H-imidazol-1′-ylmethyl)-1,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ179). To a solution of OZ145 (1.08 g, 3.1 mmol) inether (80 ml) was added 1 M ethereal HCl (3.5 ml). The resultingprecipitate was collected by filtration to afford trioxolane OZ179 (1.14g, 97%) as a colorless solid. mp 153-156° C.; ¹H NMR (500 MHz, CDCl₃) δ1.19-1.46 (m, 2H), 1.50-2.19 (m, 21H), 4.24 (br s, 2H), 7.15 (s, 1H),7.42 (s, 1H), 9.70 (s, 1H), 15.94 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃)δ 26.38, 26.77, 27.26, 33.20, 34.71, 36.29, 36.68, 37.17, 54.75, 107.85,111.62, 119.72, 121.22, 135.82. Anal. Calcd for C₂₀H₂₉ClN₂O₃: C, 63.06;H, 7.67; N, 7.35. Found: C, 63.21; H, 7.63; N, 7.30.

[0194]cis-Adamantane-2-spiro-3′-8′-[4′-(4′,5′-dihydro-4′,4′-dimethyl-2′-oxazolyl)phenyl]-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ180). To a solution of OZ154 (0.21 g, 0.48 mmol) inether (9 ml) and CH₂Cl₂ (1 ml) was added 1 M ethereal HCl (0.5 ml). Theresulting precipitate was collected by filtration to afford trioxolaneOZ180 (0.20 g, 88%) as a colorless solid. mp 143-145° C.; ¹H NMR (500MHz, CDCl₃) δ 1.58-2.25 (m, 28H), 2.58-2.80 (m, 1H), 4.69 (br s, 2H),7.44 (br s, 2H), 8.40 (br s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44,26.84, 27.19, 30.87, 34.37, 34.76, 36.39, 36.74, 43.21, 63.92, 83.36,107.83, 111.59, 117.60, 128.16, 131.38, 156.27, 168.98. Anal. Calcd forC₂₇H₃₆ClNO₄: C, 68.41; H, 7.65; N. 2.95. Found: C, 68.26; H, 7.80; N,2.90.

[0195]cis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decanecitrate (OZ181). Step 1. A solution of OZ146 (1.00 g, 2.36 mmol) andhydrazine monohydrate (0.50 g, 10 mmol) in chloroform (22.5 ml) andmethanol (2.5 ml) was heated under nitrogen at 55° C. for 25 h. Thereaction mixture was cooled to rt and filtered to remove solidby-products. The filtrate was washed with water (10 ml) and brine (10ml), dried over MgSO₄, filtered, and concentrated. The crude product waspurified by flash chromatography (silica gel, CHCl₃/MeOH/Et₃N, 90:10:1)to affordcis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decane(0.63 g, 91%) as a colorless solid. ¹H NMR (500 MHz, DMSO-d₆) δ1.14-1.22 (m, 2H), 1.30-1.40 (m, 2H), 1.60-2.10 (m, 21H), 2.55 (d, J=6.6Hz, 2H). Step 2. To a solution of the above amine (0.40 g, 1.36 mmol) inacetone (10 ml) was added a solution of citric acid (0.25 g, 1.30 mmol)in acetone (10 ml). The mixture was stirred at rt for 30 min andfiltered. The filtrate was concentrated and treated with ether (25 ml).The resulting precipitate was collected by filtration, re-dissolved inmethanol (5 ml), and concentrated to afford trioxolane OZ181 (0.30 g,45%) as a colorless solid. mp 76-77° C.; ¹H NMR (500 MHz, DMSO-d₆) δ1.04-1.21 (m, 2H), 1.56-2.04 (m, 21H), 2.53 (AB system, 4H), 2.69 (d,J=7.3 Hz, 2H), 7.78 (br s, 3H), 11.50 (br s, 2H); ¹³C NMR (125.7 MHz,DMSO-d₆) δ 25.95, 26.37, 27.10, 33.01, 33.88, 34.40, 34.42, 35.90,36.23, 43.61, 44.43, 71.35, 108.29, 110.81, 171.39. Anal. Calcd forC₂₃H₃₅NO₁₀.0.4H₂O: C, 55.52; H, 7.36; N, 2.82. Found: C, 55.25; H, 7.25;N, 2.66.

[0196]Adamantane-2-spiro-3′-8′-[[2′-(1′H-imidazol-1′-yl)ethoxy]carbonyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ182). To a solution of OZ72 (0.31 g, 1.0 mmol), triphenylphosphine(0.26 g, 1.0 mmol), and 1-(2-hydroxyethyl)imidazole (0.11 g, 1.0 mmol)in THF (10 ml) at 0° C. was added dropwise a solution of diisopropylazodicarboxylate (0.20 g, 1.0 mmol) in THF (2 ml). The mixture was thenwarmed to rt and stirred at rt for 16 h before removal of solvents. Thecrude product was purified by flash chromatography (silica gel, 1%methanol in methylene chloride) to afford trioxolane OZ182 (0.21 g, 52%,3:1 mixture of two diastereomers) as a colorless solid. mp 75-76° C.(ether/hexanes 1:1); ¹H NMR (500 MHz, CDCl₃) δ 1.60-2.18 (m, 22H),2.25-2.48 (m, 1H), 4.20 (t, J=5.3 Hz, 2H), 4.33 (t, J=5.1 Hz, 2H), 6.94(s, 1H), 7.09 (s, 1H), 7.57 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.11,26.27, 26.44, 26.47, 26.84, 26.87, 33.21, 33.40, 34.75, 34.76, 34.78,34.81, 36.35, 36.37, 36.75, 36.78, 41.15, 45.87, 63.06, 107.65,108.11,111.38, 111.61, 119.02,129.31, 137.33, 174.34. Anal. Calcd forC₂₂H₃₀N₂O₅: C, 65.65; H, 7.51; N, 6.96. Found: C, 65.86; H, 7.58; N,6.78.

[0197]cis-Adamantane-2-spiro-3′-8′-[4′-[(hydroxyamino)carbonyl]phenyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ183). A mixture of ethyl chloroformate (0.13 g, 1.2 mmol), OZ165(0.41 g, 1.0 mmol), and triethylamine (0.13 g, 1.3 mmol), ether (5 ml),THF (5 ml), and DMF (5 ml) was stirred at 0° C. for 1 h. The solid wasremoved by filtration, and the filtrate was added to a freshly preparedsolution of hydroxylamine. [To a suspension of KOH (84 mg, 1.5 mmol) inmethanol (1 ml) at 0° C. was added a solution of hydroxylaminehydrochloride (0.10 g, 1.5 mmol) in methanol (2 ml). The reactionmixture was stirred at 0° C. for 15 min and filtered to remove solidby-products. The filtrate was used as such.] The resulting mixture wasstirred at rt for 1 h and concentrated. The crude product was trituratedwith chloroform (6 ml) at 45° C. for 10 min and cooled to rt. Theprecipitate was collected by filtration and recrystallized fromchloroform/methanol (2:1) to afford trioxolane OZ183 (0.13 g, 33%) as acolorless solid. mp 167-168° C. (chloroform/methanol 2:1); ¹H NMR (500MHz, DMSO-d₆) δ 1.40-2.17 (m, 22H), 2.57-2.80 (m, 1H), 7.29 (d, J=7.8Hz, 2H), 7.67 (d, J=7.8 Hz, 2H), 8.95 (s, 1H), 11.14 (s, 1H); ¹³C NMR(125.7 MHz, DMSO-d₆) δ 26.03, 26.44, 31.06, 34.21, 34.48, 36.01, 36.30,41.61, 108.26, 110.83, 126.82, 127.25, 130.92, 149.41, 164.47. Anal.Calcd for C₂₃H₂₉NO₅: C, 69.15; H, 7.32; N, 3.51. Found: C, 68.89; H,7.30; N, 3.70.

[0198]Adamantane-2-spiro-3′-8′-[(cyclopropylmethyl)amino]-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ184). To a solution of OZ05 (555 mg, 2 mmol) in1,2-dichloroethane (10 ml) were added cyclopropanemethylamine (156 mg,2.2 mmol) and acetic acid (10 drops). The reaction mixture was stirredat rt for 15 min before sodium triacetoxyborohydride (677 mg, 3.2 mmol)was added. The mixture was stirred for 5 h before being quenched with 1M aq. NaOH (2 ml). The resulting mixture was extracted with CH₂Cl₂ (40ml), washed with water (2×10 ml) and brine (2×10 ml), dried over MgSO₄,and concentrated. The residue was dissolved in ether (2 ml), treatedwith excess 2 M ethereal HCl, and filtered to give trioxolane OZ184 (401mg, 54%, 1:1 mixture of two diastereomers) as a colorless solid. mp 110°C. dec (ether); ¹H NMR (500 MHz, CDCl₃) δ 0.39-0.60 (m, 2H), 0.61-0.85(m, 2H), 1.22-1.43 (m, 1H), 1.59-2.45 (m, 22H), 2.76-3.02 (m, 2H),3.08-3.35 (m, 1H), 9.65 (br s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 4.83,4.87, 7.06, 7.13, 25.87, 25.94, 26.37, 26.73, 26.77, 32.29, 34.67,34.70, 34.79, 36.20, 36.28, 36.66, 48.93, 49.25, 54.42, 54.60, 106.74,106.75, 111.77, 112.28. Anal. Calcd for C₂₀H₃₂ClNO₃: C, 64.94; H, 8.72;N, 3.79. Found: C, 65.18; H, 8.56; N, 3.83.

[0199]Adamantane-2-spiro-3′-8′-(cyclopropylamino)-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ185). To a solution of OZ05 (555 mg, 2 mmol) in1,2-dichloroethane (10 ml) were added cyclopropylamine (125 mg, 2.2mmol) and acetic acid (10 drops). The reaction mixture was stirred at rtfor 15 min before sodium triacetoxyborohydride (677 mg, 3.2 mmol) wasadded. The mixture was stirred for 5 h before being quenched with 1 Maq. NaOH (2 ml). The resulting mixture was extracted with CH₂Cl₂ (40ml), washed with water (2×10 ml) and brine (2×10 ml), dried over MgSO₄,and concentrated. The residue was dissolved in ether (2 ml), treatedwith excess 2 M ethereal HCl, and filtered to give trioxolane OZ185 (348mg, 49%, 1:1 mixture of two diastereomers) as a colorless solid. mp102-103° C. dec (ether); ¹H NMR (500 MHz, CDCl₃) δ 0.69-1.05 (m, 2H),1.20-1.45 (m, 2H), 1.59-2.21 (m, 20H), 2.22-2.45 (m, 2H), 2.46-2.69 (m,1H), 3.01-3.39 (m, 1H), 9.62 (br s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ3.85, 26.21, 26.24, 26.40, 26.76, 26.80, 27.49, 27.94, 32.35, 34.70,34.73, 34.86, 36.24, 36.32, 36.70, 56.85, 57.19, 106.76, 106.78, 111.84,112.34. Anal. Calcd for C₁₉H₃₀ClNO₃: C, 64.12; H, 8.50; N, 3.94. Found:C, 64.00; H, 8.38; N, 3.84.

[0200]cis-Adamantane-2-spiro-3′-8′-[(methoxyacetyl)amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ186). To a solution of OZ137 (550 mg, 1.74 mmol) in CH₂Cl₂ (10 ml) at0° C. were added triethylamine (350 mg, 3.48 mmol) and methoxyacetylchloride (198 mg, 1.82 mmol). The resulting mixture was stirred at rtfor 16 h, diluted with CH₂Cl₂ (10 ml), and washed with water (10 ml) andbrine (10 ml). The organic layer was separated, dried over MgSO₄, andconcentrated. The crude product was purified by flash chromatography(silica gel, 85% ether in hexanes) to give trioxolane OZ186 (379 mg,62%) as a colorless solid. mp 105-106° C. (ether); ¹H NMR (500 MHz,CDCl₃) δ 1.40-1.61 (m, 2H), 1.62-2.21 (m, 20H), 3.41 (s, 3H), 3.86 (s,2H), 3.80-3.96 (m, 1H), 6.35-6.49 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.34, 26.72, 29.67, 32.56, 34.64, 36.20, 36.63, 45.84, 58.94, 71.83,107.53, 111.47, 168.65. Anal. Calcd for C₁₉H₂₉NO₅: C, 64.93; H, 8.32; N,3.99. Found: C, 64.81; H, 8.31; N, 3.91.

[0201]cis-Adamantane-2-spiro-3′-8′-[[(dimethylamino)carbonyl]amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ187). To a solution of OZ137 (550 mg, 1.74 mmol) in CH₂Cl₂ (10 ml) at0° C. were added triethylamine (352 mg, 3.48 mmol) and dimethylcarbamoylchloride (197 mg, 1.82 mmol). The resulting mixture was stirred at rtfor 16 h, diluted with CH₂Cl₂ (10 ml), and washed with water (10 ml) andbrine (10 ml). The organic layer was separated, dried over MgSO₄, andconcentrated. The crude product was purified by flash chromatography(silica gel, 90% ether in hexanes) to give trioxolane OZ187 (346 mg,57%) as a colorless solid. mp 142-144° C. (ether); ¹H NMR (500 MHz,CDCl₃) δ 1.32-1.55 (m, 2H), 1.62-2.21 (m, 20H), 2.88 (s, 6H), 3.62-3.85(m, 1H), 4.15-4.29 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.42, 26.79,30.67, 32.86, 34.72, 36.07, 36.28, 36.72, 47.91, 107.94, 111.45, 157.69.Anal. Calcd for C₁₉H₃₀N₂O₄: C, 65.12; H, 8.63; N, 7.99. Found: C, 65.30;H, 8.68; N, 8.06.

[0202]Adamantane-2-spiro-3′-8′-(4′-morpholinylcarbonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ188). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (202mg, 2 mmol) in CH₂Cl₂ (7 ml) at 0° C. was added 4-morpholinecarbonylchloride (170 mg, 1.1 mmol). The mixture was stirred at rt for 16 h,diluted with CH₂Cl₂ (10 ml), washed with water (2×10 ml) and brine (10ml), dried over MgSO₄, and concentrated. Crystallization of the residuefrom ethanol gave trioxolane OZ188 (310 mg, 82%) as a colorless solid.mp 132-134° C. (ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.60-2.21 (m, 18H),3.18-3.28 (m, 4H), 3.29-3.58 (m, 4H), 3.60-3.82 (m, 4H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.42, 26.82, 34.37, 34.73, 34.82, 36.39, 36.70, 44.59,47.41, 66.62, 107.03, 112.04, 163.66. Anal. Calcd for C₂₀H₃₀N₂O₅: C,63.47; H, 7.99; N, 7.40. Found: C, 63.24; H, 7.84; N, 7.44.

[0203]cis-Adamantane-2-spiro-3′-8′-[2′-(4′-morpholinyl)-2′-oxoethyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ189). To a solution of OZ78 (322 mg, 1.0 mmol) in ether (10 ml) at 0°C. were added triethylamine (202 mg, 2 mmol) and ethyl chloroformate(217 mg, 2 mmol). The mixture was stirred at 0° C. for 15 min beforemorpholine (175 mg, 2 mmol) was added. The resulting mixture was stirredat rt for 12 h, diluted with ether (10 ml), washed with water (10 ml),dried over MgSO₄, and concentrated. The crude product was purified bycrystallization from ethanol to afford trioxolane OZ189 (290 mg, 74%) asa colorless solid. mp 118-120° C. (ethanol); ¹H NMR (500 MHz, CDCl₃) δ1.16-1.35 (m, 2H), 1.60-2.16 (m, 21H), 2.21 (d, J=6.9 Hz, 2H), 3.38-3.54(m, 2H), 3.55-3.82 (m, 6H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.48, 26.86,30.28, 33.26, 34.05, 34.79, 36.39, 36.79, 39.01, 41.93, 46.18, 66.66,66.97, 108.58, 111.35, 170.67. Anal. Calcd for C₂₂H₃₃NO₅: C, 67.49; H,8.50; N, 3.58. Found: C, 67.46; H, 8.39; N, 3.34.

[0204]Adamantane-2-spiro-3′-8′-(dimethylaminosulfonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ190). To a stirred solution of OZ80 (301 mg, 1 mmol) in CH₂Cl₂ (10ml) at rt were added triethylamine (0.4 ml, 3 mmol) anddimethylaminosulfonyl chloride (0.13 ml, 1.2 mmol). The mixture wasstirred at rt for 3 h before removal of the solvent. The residue wasdiluted with ether (15 ml), washed with water (2×10 ml), dried overMgSO₄, and concentrated. Crystallization of the residue fromether/hexanes (1:1) gave trioxolane OZ190 (301 mg, 81%) as a colorlesssolid. mp 104-106° C. (ether/hexanes 1:1); ¹H NMR (500 MHz, CDCl₃) δ1.62-2.17 (m, 18H), 2.82 (s, 6H), 3.29-3.53 (m, 4H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.40, 26.79, 34.24, 34.71, 34.80, 36.36, 36.67, 38.18, 44.51,106.23, 112.25. Anal. Calcd for C₁₇H₂₉N₂O₅S: C, 54.82; H, 7.58; N, 7.52.Found: C, 54.70; H, 7.38; N, 7.50.

[0205]Adamantane-2-spiro-3′-8′-amidino-1′,2′,4′-trioxa-8′-azaspiro[4.5]decanehydrochloride (OZ191). To a stirred solution of OZ80 (301 mg, 1 mmol)and triethylamine (202 mg, 2 mmol) in DMF (2 ml) and CH₂Cl₂ (2 ml) at rtwas added N,N-diisopropylethylamine (130 mg, 2 mmol). After1H-pyrazole-1-carboxamidine hydrochloride (147 mg, 1 mmol) was added,the reaction mixture became a cloudy suspension. The stirring wascontinued for 3 h during which period the reaction mixture turned into aclear solution. Addition of dry ether (15 ml) to the above solutionproduced a colorless precipitate, which was then filtered and washedwith ether (3×5 ml). The collected solid was recrystallized fromether/CH₂Cl₂ (3:1) to give trioxolane OZ191 (302 mg, 88%) as a colorlesssolid. mp 144-148° C. (ether/CH₂Cl₂, 3:1); ¹H NMR (500 MHz, DMSO-d₆) δ1.57-2.17 (m, 18H), 3.41-3.69 (m, 4H), 7.72 (s, 4H); ¹³C NMR (125.7 MHz,DMSO-d₆) δ 25.93, 26.31, 33.61, 34.38, 34.43, 35.76, 36.15, 43.39,106.29, 111.74, 156.36. Anal. Calcd for C₁₆H₂₆ClN₃O₃: C, 55.89; H, 7.62;N, 12.22. Found: C, 55.73; H, 7.54; N, 12.23.

[0206]Adamantane-2-spiro-3′-8′-[(4′-chlorophenylamino)carbonyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ192). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (202mg, 2 mmol) in CH₂Cl₂ (7 ml) at 0-5° C. was added 4-chlorophenylisocyanate (154 mg, 1 mmol). The reaction mixture was stirred at rt for16 h, diluted with CH₂Cl₂ (10 ml), and washed with water (2×10 ml) andbrine (10 ml). The organic layer was dried over MgSO₄ and concentrated.The residue was purified by crystallization from methanol to affordtrioxolane OZ192 (346 mg, 83%) as a colorless solid. mp 132-134° C.(methanol); ¹-H NMR (500 MHz, CDCl₃) δ 1.61-2.17 (m, 18H), 3.42-3.77 (m,4H), 6.43 (s, 1H), 7.17-7.37 (m, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.41, 26.81, 34.34, 34.73, 34.82, 36.38, 36.67, 42.34, 106.65, 112.32,121.19, 128.20, 128.86, 137.53, 154.46. Anal. Calcd for C₂₂H₂₇ClN₂O₄: C,63.08; H, 6.50; N, 6.69. Found: C, 62.95; H, 6.36; N, 6.65.

[0207]Adamantane-2-spiro-3′-8′-(4′-fluorophenoxy)-1′,2′,4′-trioxaspiro[4.5]decane(OZ193). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol)and 4-(4-fluorophenoxy)cyclohexanone (950 mg, 5.1 mmol) in cyclohexane(80 ml) and CH₂Cl₂ (20 ml) was treated with ozone according to thegeneral procedure. The crude product was purified by flashchromatography (silica gel, 5% ether in hexanes) and by subsequentrecrystallization from ethanol/CH₂Cl₂ (19:1) to afford trioxolane OZ193(250 mg, 13%) as a colorless solid. mp 102-104° C. (ethanol/CH₂Cl₂19:1); ¹H NMR (500 MHz, CDCl₃) δ 1.57-2.21 (m, 22H), 4.29-4.41 (m, 1H),6.79-6.89 (m, 2H), 6.91-7.05 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.48, 26.88, 27.82, 30.06, 34.79, 34.85, 36.43, 36.79, 72.54, 108.22,111.71, 115.87 (d, J=23.3 Hz), 117.44 (d, J=8.2 Hz), 153.44, 157.34 (d,J=239.0 Hz). Anal. Calcd for C₂₂H₂₇FO₄: C, 70.57; H, 7.27. Found: C,70.71; H, 7.33.

[0208]Adamantane-2-spiro-3′-8′-[(diisopropylamino)carbonyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ194). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (303mg, 3 mmol) in CH₂Cl₂ (10 ml) at 0-5° C. was added diisopropylcarbamoylchloride (164 mg, 1 mmol). The resulting mixture was stirred at rt for16 h, diluted with CH₂Cl₂ (10 ml), and washed with water (2×10 ml) andbrine (10 ml). The organic layer was dried over MgSO₄ and concentrated.The residue was purified by crystallization from methanol to affordtrioxolane OZ194 (290 mg, 74%) as a colorless solid. mp 114-116° C.(methanol); ¹-H NMR (500 MHz, CDCl₃) δ 1.27 (d, J=6.8 Hz, 12H),1.60-2.21 (m, 18H), 3.11-3.39 (m, 4H), 3.60 (sep, J=6.6 Hz, 2H); ¹³C NMR(125.7 MHz, CDCl₃) δ 21.57, 26.44, 26.84, 34.39, 34.72, 34.81, 36.40,36.73, 45.26, 47.52, 107.29, 111.79, 163.59. Anal. Calcd for C₂₂H₃₆N₂O₄:C, 67.32; H, 9.24; N, 7.14. Found: C, 67.14; H, 9.13; N, 7.11.

[0209]cis-Adamantane-2-spiro-3′-8′-[(tert-butylacetyl)amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ195). To a solution of OZ137 (550 mg, 1.74 mmol) in CH₂Cl₂ (10 ml) at0° C. were added triethylamine (529 mg, 5.22 mmol) and tert-butylacetylchloride (304 mg, 2.26 mmol). The resulting mixture was stirred at rtfor 16 h, diluted with CH₂Cl₂ (10 ml), and washed with water (10 ml) andbrine (10 ml). The organic layer was separated, dried over MgSO₄, andconcentrated. The crude product was purified by flash chromatography(silica gel, 75% ether in hexanes) to give trioxolane OZ195 (335 mg,51%) as a colorless solid. mp 142-144° C. (ether); ¹H NMR (500 MHz,CDCl₃) δ 1.02 (s, 9H), 1.30-1.51 (m, 2H), 1.52-1.99 (m, 20H), 1.96 (s,2H), 3.79-3.95 (m, 1H), 5.23-5.28 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.44, 26.82, 29.77, 30.00, 30.79, 32.76, 34.76, 36.31, 36.74, 46.45,50.69, 107.76, 111.63, 170.97. Anal. Calcd for C₂₂H₃₅NO₄: C, 69.99; H,9.34; N, 3.71. Found: C, 70.15; H, 9.38; N, 3.65.

[0210]cis-Adamantane-2-spiro-3′-8′-[(3′-carboxy-1′-oxopropyl)amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ196). To a solution of OZ137 (550 mg, 1.74 mmol) in CH₂Cl₂ (10 ml) at0° C. were added triethylamine (350 mg, 3.48 mmol) and succinicanhydride (176 mg, 1.74 mmol). The resulting mixture was stirred at rtfor 24 h, concentrated, and triturated with water (3×10 ml), hexanes(2×10 ml), and THF (5 ml) to give trioxolane OZ196 (350 mg, 53%) as acolorless solid. mp 122-124° C. (THF); ¹H NMR (500 MHz, DMSO-d₆) δ1.33-1.57 (m, 2H), 1.62-2.19 (m, 20H), 2.31-2.41 (m, 2H), 2.42-2.57 (m,2H), 3.65-3.82 (m, 1H), 7.83-7.87 (m, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆)δ 26.00, 26.39, 29.34, 29.43, 32.20, 34.43, 35.88, 36.26, 45.65, 108.07,110.81, 170.41, 173.99. Anal. Calcd for C₂₀H₂₉NO₆: C, 63.31; H, 7.70; N,3.69. Found: C, 63.46; H, 7.68; N, 3.84.

[0211]cis-Adamantane-2-spiro-3′-8′-[(2′,5′-dioxo-1′-pyrrolidinyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ197). To a solution of OZ119 (0.29 g, 1 mmol), triphenylphosphine(0.42 g, 1.6 mmol), and succinimide (0.11 g, 1.1 mmol) in THF (6 ml) at0° C. was added a solution of DIPAD (0.32 g, 1.6 mmol) in THF (1 ml).The mixture was warmed to rt and stirred overnight. After removal of thesolvent, the crude product was purified by flash chromatography (silicagel, 25% ether in hexanes) and by subsequent recrystallization fromhexanes/CH₂Cl₂ (3:1) to give trioxolane OZ197 (0.30 g, 80%) as acolorless solid. mp 147-148° C. (hexanes/CH₂Cl₂ 3:1); ¹H NMR (500 MHz,CDCl₃) δ 1.37-1.59 (m, 2H), 1.61-2.35 (m, 21H), 2.92 (s, 4H), 3.59 (d,J=7.1 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.39, 26.79, 27.70, 28.02,33.46, 34.69, 34.71, 34.74, 36.28, 36.71, 43.75, 108.32, 111.25, 177.26.Anal. Calcd for C₂₁H₂₉NO₅: C, 67.18; H, 7.79; N, 3.73. Found: C, 67.12;H, 7.81; N, 3.63.

[0212]cis-Adamantane-2-spiro-3′-8′-(3′-carboxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ198). A mixture of OZ208 (0.38 g, 0.92 mmol), KOH (0.36 g), THF (10ml), methanol (10 ml), and water (2 ml) was heated at 50° C. for 2 h.The mixture was concentrated, diluted with water (10 ml), and acidifiedwith 1 M aq. HCl to pH=2. The resulting solid was collected byfiltration and washed with hexanes/ether (10 ml, 2:1) to give trioxolaneOZ198 (0.28 g, 79%) as a colorless solid. mp 150-152° C.; ¹H NMR (500MHz, CDCl₃) δ 1.63-2.22 (m, 22H), 2.58-2.73 (m, 1H), 7.40 (dd, J=7.7,7.7 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.97 (s,1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.51, 26.91, 31.31, 34.63, 34.82,36.43, 36.82, 42.72, 108.21, 111.49, 128.13, 128.60, 128.75, 129.46,132.06, 146.59, 171.58. Anal. Calcd for C₂₃H₂₈O₅: C, 71.85; H, 7.34.Found: C, 71.74; H, 7.30.

[0213]Adamantane-2-spiro-3′-8′-carbamoyl-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ199). To a solution of OZ80 (450 mg, 1.49 mmol) in CH₂Cl₂ (12 ml) atrt were added pyridine (1.2 ml, 14.9 mmol), HOAc (0.82 ml, 14.9 mmol),triethylamine (0.4 ml, 2.98 mmol), and potassium cyanate (243 mg, 2.98mmol). After being stirred for 35 h the reaction mixture was poured intoa mixture of ether (50 ml) and water (50 ml). The organic layer wasseparated, washed with brine (15 ml), dried over MgSO₄, andconcentrated. Crystallization of the residue from ether/CH₂Cl₂ (3:1)afforded trioxolane OZ199 (449 mg, 98%) as a colorless solid. mp140-142° C. (ether/CH₂Cl₂ 3:1); ¹H NMR (500 MHz, CDCl₃) δ 1.57-2.21 (m,18H), 3.31-3.69 (m, 4H), 4.55 (s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.41, 26.81, 34.27, 34.73, 34.81, 36.37, 36.69, 42.25, 106.72, 112.21,157.65. Anal. Calcd for C₁₆H₂₄N₂O₄.0.4H₂O: C, 60.89; H, 7.92; N, 8.88.Found: C, 60.86; H, 7.60; N, 8.84.

[0214]Adamantane-2-spiro-3′-8′-[2′-(ethylsulfonyl)ethyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ200). To a stirred solution of OZ80 (450 mg, 1.49 mmol) in CH₂Cl₂ (10ml) and methanol (10 ml) at rt was added triethylamine (0.4 ml, 2.98mmol) followed by ethyl vinyl sulfone (0.15 ml, 1.49 mmol). Theresulting mixture was stirred at rt for 3 h before removal of thesolvents. The residue was diluted with ether (15 ml), washed with water(2×10 ml), dried (MgSO₄), and concentrated. Crystallization of the crudeproduct from ether/hexanes (1:1) afforded trioxolane OZ200 (415 mg, 72%)as a colorless solid. mp 105-107° C. (ether/hexanes 1:1); ¹H NMR (500MHz, CDCl₃) δ 1.39 (t, J=7.6 Hz, 3H), 1.57-2.21 (m, 18H), 2.41-2.59 (m,2H), 2.60-2.78 (m, 2H), 2.89 (t, J=6.5 Hz, 2H), 3.09 (t, J=6.5 Hz, 2H),3.14 (q, J=7.4 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 6.59, 26.40, 26.80,34.33, 34.71, 34.79, 36.34, 36.69, 48.56, 49.74, 50.94, 51.10, 106.54,111.85. Anal. Calcd for C₁₉H₃₁NO₅S: C, 59.19; H, 8.10; N, 3.63. Found:C, 58.98; H, 7.95; N, 3.65.

[0215]cis-Adamantane-2-spiro-3′-8′-[(4′-fluorophenyl)amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ201). To a solution of OZ05 (555 mg, 2 mmol) in 1,2-dichloroethane(10 ml) were added 4-fluoroaniline (236 mg, 2.12 mmol) and acetic acid(10 drops). The reaction mixture was stirred at rt for 15 min beforesodium triacetoxyborohydride (677 mg, 3.2 mmol) was added. The mixturewas stirred for 5 h before being quenched with 1 M aq. NaOH (2 ml). Theresulting mixture was extracted with CH₂Cl₂ (40 ml), washed with water(2×10 ml) and brine (2×10 ml), dried over MgSO₄, and concentrated togive an oil (517 mg, 69%, 2:1 mixture of two diastereomers). Triturationwith ether and hexanes gave trioxolane OZ201 (280 mg, 37%) as acolorless solid. mp 118-120° C. (hexanes); ¹H NMR (500 MHz, CDCl₃) δ1.37-1.52 (m, 2H), 1.53-2.21 (m, 20H), 3.19-3.27 (m, 1H), 3.28-3.49 (m,1H), 6.41-6.63 (m, 2H), 6.77-6.99 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃)?26.46, 26.87, 30.10, 32.75, 34.77, 34.81, 36.34, 36.76, 50.92, 108.08,111.58, 114.14 (d, J=7.3 Hz), 115.71 (d, J=22.4 Hz), 143.44, 155.70 (d,J=234.9 Hz). Anal. Calcd for C₂₂H₂₈FNO₃: C, 70.75; H, 7.56; N, 3.75.Found: C, 70.85; H, 7.42; N, 3.76.

[0216]cis-Adamantane-2-spiro-3′-8′-[(2′-acetoxy-2′-methylpropionyl)amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ202). To a solution of OZ137 (550 mg, 1.74 mmol) in CH₂Cl₂ (10 ml) at0° C. were added triethylamine (529 mg, 5.22 mmol) and2-acetoxy-2-methylpropionyl chloride (430 mg, 2.61 mmol). The resultingmixture was stirred at rt for 16 h, diluted with CH₂Cl₂ (10 ml), andwashed with water (10 ml) and brine (10 ml). The organic layer wasseparated, dried over MgSO₄, and concentrated. The crude product waspurified by trituration with hexanes to give trioxolane OZ202 (350 mg,49%) as a colorless solid. mp 130-132° C. (hexanes); ¹H NMR (500 MHz,CDCl₃) δ 1.35-1.52 (m, 2H), 1.61 (s, 6H), 1.62-2.06 (m, 20H), 2.07 (s,3H), 3.75-3.95 (m, 1H), 5.77-5.93 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ21.87, 24.29, 26.43, 26.81, 29.73, 32.68, 34.75, 36.30, 36.73, 46.51,81.35, 107.66, 111.65, 169.15, 172.35. Anal. Calcd for C₂₂H₃₃NO₆: C,64.84; H, 8.16; N, 3.44. Found: C, 64.80; H, 7.93; N, 3.52.

[0217]Adamantane-2-spiro-3′-8′-(1′-pyrrolidinylcarbonyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ203). To a solution of OZ80 (301 mg, 1 mmol) and triethylamine (303mg, 3 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added 1-pyrrolidinecarbonylchloride (118 mg, 1 mmol). The mixture was stirred at rt for 16 h,diluted with CH₂Cl₂ (10 ml), and washed with water (2×10 ml) and brine(10 ml). The organic layer was separated, dried over MgSO₄, andconcentrated. Crystallization of the residue from methanol gavetrioxolane OZ203 (152 mg, 42%) as a colorless solid. mp 130-132° C.(methanol); ¹H NMR (500 MHz, CDCl₃) δ 1.61-2.15 (m, 22H), 3.23-3.57 (m,8H); ¹³C NMR (125.7 MHz, CDCl₃).25.53, 26.44, 26.83, 34.51, 34.73,34.82, 36.40, 36.72, 43.94, 48.38, 107.26, 111.90, 162.56. Anal. Calcdfor C₂₀H₃₀N₂O₄: C, 66.27; H, 8.34; N, 7.73. Found: C, 66.33; H, 8.30; N,7.60.

[0218]cis-Adamantane-2-spiro-3′-8′-[(4′-methoxycarbonylphenyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ204). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol)and 4-[(4-methoxycarbonylphenyl)methyl]cyclohexanone (1.27 g, 5 mmol) incyclohexane (80 ml) and CH₂Cl₂ (20 ml) was treated with ozone accordingto the general procedure. The crude product was purified by flashchromatography (silica gel, 5% ether in hexanes) and subsequentrecrystallization from ethanol/CH₂Cl₂ (19:1) to afford trioxolane OZ204(950 mg, 46%) as a colorless solid. mp 104-106° C. (ethanol/CH₂Cl₂19:1); ¹H NMR (500 MHz, CDCl₃) δ 1.19-1.37 (m, 2H), 1.49-2.07 (m, 21H),2.56 (d, J=6.9 Hz, 2H), 3.90 (s, 3H), 7.20 (d, J=7.9 Hz, 2H), 7.95 (d,J=7.9 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.48, 26.87, 29.90, 34.08,34.78, 36.38, 36.80, 38.00, 42.86, 51.95, 108.76, 111.28, 127.91,129.08, 129.57, 146.42, 167.12. Anal. Calcd for C₂₅H₃₂O₅: C, 72.79; H,7.82. Found: C, 72.72; H, 7.85.

[0219]cis-Adamantane-2-spiro-3′-8′-(2′-hydroxy-2′-methylpropyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ205). To a solution of OZ61 (350 mg, 1 mmol) in CH₂Cl₂ at −78° C. wasadded methyllithium (3 ml, 1.6 M in ether, 4.8 mmol). The reaction wasstirred at −78° C. for 2 h before being quenched with water. The organiclayer was separated, and the aqueous layer was extracted with CH₂Cl₂(2×10 ml). The combined organic layers were washed with water (10 ml)and brine (10 ml), dried over MgSO₄, filtered, and concentrated. Thecrude product was purified by crystallization from ethanol to affordtrioxolane OZ205 (262 mg, 78%) as a colorless solid. mp 96-98° C.(ethanol); ¹H NMR (500 MHz, CDCl₃).1.23 (s, 6H), 1.21-1.37 (m, 2H), 1.40(d, J=5.5 Hz, 2H), 1.43-1.61 (m, 1H), 1.62-2.09 (m, 20H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.49, 26.89, 30.03, 31.99, 32.47, 34.31, 34.78, 34.80,36.40, 36.82, 49.76, 71.39, 108.62, 111.17. Anal. Calcd for C₂₀H₃₂O₄: C,71.39; H, 9.59. Found: C, 71.44; H, 9.39.

[0220]cis-Adamantane-2-spiro-3′-8′-[(2′,4′-dioxo-3′-imidazolidinyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ206). To a solution of OZ119 (0.29 g, 1 mmol), triphenylphosphine(0.42 g, 1.6 mmol), and hydantoin (0.11 g, 1.1 mmol) in DMF (6 ml) andTHF (6 ml) at 0° C. was added a solution of DIPAD (0.32 g, 1.6 mmol) inTHF (1 ml). The mixture was warmed to rt and stirred overnight. Afterremoval of the solvents, the crude product was purified by flashchromatography (silica gel, 25% acetone in hexanes) and subsequentrecrystallization from hexanes/CH₂Cl₂ (5:1) to give trioxolane OZ206(0.21 g, 56%) as a colorless solid. mp 158-160° C. (hexanes/CH₂Cl₂ 5:1);¹H NMR (500 MHz, CDCl₃) δ 1.21-1.41 (m, 2H), 1.58-2.19 (m, 21H), 3.40(d, J=6.9 Hz, 2H), 3.99 (s, 2H), 5.81 (s, 1H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.47, 26.87, 27.69, 33.54, 34.77, 34.79, 35.10, 36.36, 36.79,43.76, 46.27, 108.43, 111.36, 158.35, 171.31. Anal. Calcd forC₂₀H₂₈N₂O₅: C, 63.81; H, 7.50; N, 7.44. Found: C, 63.68; H, 7.31; N,7.39.

[0221]cis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ207). To a solution ofcis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decane(1.465 g, 5 mmol) in ether (60 ml) and CH₂Cl₂ (20 ml) was added asolution of p-TsOH (0.96 g, 5 mmol) in ether (80 ml). The resultingmixture was placed at −20° C. overnight. The solid was collected byfiltration to afford trioxolane OZ207 (2.24 g, 96%) as a colorlesssolid. mp 162-164° C.; ¹H NMR (500 MHz, DMSO-d₆) 81.01-1.23 (m, 2H),1.51-2.07 (m, 21H), 2.29 (s, 3H), 2.68 (app t, J=5.7 Hz, 2H), 7.12 (d,J=7.8 Hz, 2H), 7.48 (d, J=8.3 Hz, 2H), 7.68 (br s, 3H); ¹³C NMR (125.7MHz, DMSO-d₆) δ 20.93, 25.95, 26.36, 27.08, 32.99, 33.86, 34.40, 34.41,35.89, 36.22, 43.63, 108.28, 110.80, 125.65, 128.21, 137.77, 145.87.Anal. Calcd for C₂₄H₃₅NO₆S: C, 61.91; H, 7.58; N, 3.01. Found: C, 61.78;H, 7.38; N, 2.97.

[0222]cis-Adamantane-2-spiro-3′-8′-[(3′-ethoxycarbonyl)phenyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ208). A solution of O-methyl 2-adamantanone oxime (0.65 g, 2.6 mmol)and 4-[3-(ethoxycarbonyl)phenyl]cyclohexanone (0.47 g, 2.6 mmol) inpentane (50 ml) and CH₂Cl₂ (25 ml) was treated with ozone according tothe general procedure. The crude product was purified by flashchromatography (silica gel, 10% ether in hexanes) to afford trioxolaneOZ208 (0.50 g, 47%) as a colorless solid. mp 72-73° C. (95% ethanol); ¹HNMR (500 MHz, CDCl₃) δ 1.39 (t, J=7.1 Hz, 3H), 1.61-2.21 (m, 22H),2.55-2.69 (m, 1H), 4.37 (q, J=7.1 Hz, 2H), 7.35 (dd, J=7.6, 7.6 Hz, 1H),7.39 (d, J=7.7 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.89 (s, 1H); ¹³C NMR(125.7 MHz, CDCl₃) δ 14.35, 26.50, 26.90, 31.33, 34.64, 34.81, 36.43,36.81, 42.78, 60.90, 108.24, 111.47, 127.48, 127.98, 128.41, 130.62,131.21, 146.38, 166.70. Anal. Calcd for C₂₅H₃₂O₅: C, 72.79; H, 7.82.Found: C, 72.61; H, 7.60.

[0223]cis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ209). To a solution ofcis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decane(0.30 g, 1.02 mmol) in ether (10 ml) and CH₂Cl₂ (5 ml) was added asolution of methanesulfonic acid (0.10 g, 1.04 mmol) in ether (30 ml).The resulting mixture was concentrated to 10 ml and placed at −20° C.overnight. The solid was collected by filtration to afford trioxolaneOZ209 (0.34 g, 86%) as a colorless solid. mp 146-148° C.; ¹H NMR (500MHz, DMSO-d₆) δ 1.01-1.23 (m, 2H), 1.51-2.07 (m, 21H), 2.34 (s, 3H),2.69 (app t, J=6.0 Hz, 2H), 7.70 (br s, 3H); ¹³C NMR (125.7 MHz,DMSO-d₆) δ 25.95, 26.36, 27.09, 33.01, 33.85, 34.39, 34.41, 35.89,36.22, 43.61, 108.28, 110.79. Anal. Calcd for C₁₈H₃₁NO₆S: C, 55.50; H,8.02; N, 3.60. Found: C, 55.41; H, 7.94; N, 3.58.

[0224]cis-Adamantane-2-spiro-3′-8′-[(phenylsulfonyl)methyl]-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ210). A solution of O-methyl 2-adamantanone oxime (1.79 g, 10 mmol)and 4-[(phenylsulfonyl)methyl]cyclohexanone (1.20 g, 4.76 mmol) inpentane (50 ml) and CH₂Cl₂ (25 ml) was treated with ozone according tothe general procedure. The crude product was purified by flashchromatography (silica gel, 33% ether in hexanes) to afford trioxolaneOZ210 (0.78 g, 39%) as a colorless solid. mp 120-122° C. (ether/hexanes1:1); ¹H NMR (500 MHz, CDCl₃) δ 1.25-1.46 (m, 2H), 1.60-2.21 (m, 21H),2.99 (d, J=6.3 Hz, 2H), 7.54-7.62 (m, 2H), 7.63-7.70 (m, 1H), 7.88-7.96(m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44, 26.83, 30.11, 31.19, 33.69,34.75, 34.76, 36.35, 36.75, 61.79, 107.77, 111.53, 127.73, 129.32,133.63, 140.21. Anal. Calcd for C₂₃H₃₀O₅S: C, 66.00; H, 7.22. Found: C,66.15; H, 7.10.

[0225]cis-Adamantane-2-spiro-3′-8′-(1′H-pyrazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ211). To a suspension of 60% NaH (0.08 g, 2 mmol) in DMF (4 ml) undernitrogen at 0° C. was added a solution of pyrazole (0.14 g, 2 mmol) inDMF (4 ml). The mixture was stirred for 30 min before a solution of themethanesulfonate of OZ119 (0.37 g, 1.0 mmol) in DMF (4 ml) was addeddropwise. The reaction mixture was heated at 50° C. for 2 h, quenchedwith water (40 ml), and then extracted with ethyl acetate (3×30 ml). Thecombined extracts were washed with brine (3×30 ml), dried over MgSO₄,filtered, and concentrated. The crude product was purified by flashchromatography (silica gel, 33% ether in hexanes) to afford trioxolaneOZ211 (0.28 g, 81%) as a colorless solid. mp 103-106° C.(hexanes/CH₂Cl₂, 4:1); ¹H NMR (500 MHz, CDCl₃) δ 1.19-1.37 (m, 2H),1.53-2.18 (m, 21H), 3.77 (d, J=7.1 Hz, 2H), 6.22 (s, 1H), 7.33 (s, 1H),7.51 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.47, 26.85, 27.63, 33.60,34.77, 36.37, 36.78, 37.16, 57.46, 105.02, 108.52, 111.43, 129.63,139.41. Anal. Calcd for C₂₀H₂₈N₂O₃: C, 69.74; H, 8.19; N, 8.13. Found:C, 69.88; H, 8.18; N, 8.17.

[0226]cis-Adamantane-2-spiro-3′-8′-[(1′,1′-dioxido-3′-oxo-1′,2′-benzisothiazol-2′(3′H)-yl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ212). To a solution of OZ119 (0.29 g, 1 mmol), triphenylphosphine(0.42 g, 1.6 mmol), and saccharin (0.20 g, 1.1 mmol) in THF (10 ml) at0° C. was added a solution of DIPAD (0.32 g, 1.6 mmol) in THF (1 ml).The mixture was warmed to rt and stirred overnight. After removal of thesolvent, the crude product was purified by flash chromatography (silicagel, 25% ether in hexanes) and by subsequent recrystallization fromhexanes/CH₂Cl₂ (4:1) to give trioxolane OZ212 (0.17 g, 37%) as acolorless solid. mp 152-155° C. (hexanes/CH₂Cl₂, 4:1); ¹H NMR (500 MHz,CDCl₃) δ 1.23-1.45 (m, 2H), 1.59-2.18 (m, 21H), 3.63 (d, J=7.4 Hz, 2H),7.80-7.90 (m, 2H), 7.93 (d, J=7.1 Hz, 1H), 8.06 (d, J=7.4 Hz, 1H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.49, 26.88, 27.79, 33.50, 34.79, 34.80,35.14, 36.39, 36.81, 44.49, 108.43, 111.39, 120.93, 125.22, 127.33,134.31, 134.73, 137.64, 159.26. Anal. Calcd for C₂₄H₂₉NO₆S: C, 62.73; H,6.36; N, 3.05. Found: C, 62.74; H, 6.18; N, 3.02.

[0227]cis-Adamantane-2-spiro-3′-8′-[[(methoxyamino)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ213). To a solution of OZ78 (322 mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0°C. were added triethylamine (202 mg, 2 mmol) and ethyl chloroformate(217 mg, 2 mmol). After the mixture was stirred at 0° C. for 15 min,methoxylamine was added. [To a suspension of methoxylamine hydrochloride(167 mg, 2 mmol) in methanol (5 ml) was added NaHCO₃ (164 mg, 2 mmol).The mixture was stirred at rt for 15 min]. The resulting mixture wasstirred at rt for 12 h, diluted with CH₂Cl₂ (10 ml), washed with water(10 ml), dried over MgSO₄, and concentrated. The crude product waspurified by crystallization from methanol to afford trioxolane OZ213(0.17 g, 48%) as a colorless solid. mp 72-74° C. (methanol); ¹H NMR (500MHz, DMSO-d₆) δ 0.99-1.21 (m, 2H), 1.45-2.11 (m, 23H), 3.56 (s, 3H),10.93 (s, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.96, 26.37, 29.54,32.64, 33.50, 34.40, 35.91, 36.25, 38.86, 63.34, 108.49, 110.64, 168.09.Anal. Calcd for C₁₉H₂₉NO₅: C, 64.93; H, 8.32; N, 3.99. Found: C, 64.79;H, 8.13; N, 3.76.

[0228]cis-Adamantane-2-spiro-3′-8′-[(4′-carboxyphenyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ214). A mixture of OZ204 (412 mg, 1 mmol), NaOH (120 mg, 3 mmol),methanol (10 ml), and water (10 ml) was stirred at rt for 16 h. Afterremovel of the solvents, the residue was acidified with 6 M aq. HCl (4ml) to pH=2, and the resulting precipitate was collected by filtrationand further crystallized from 95% ethanol to give trioxolane OZ214 (182mg, 46%) as a colorless solid. mp 160-162° C. (95% ethanol); ¹H NMR (500MHz, CDCl₃) δ 51.09-1.39 (m, 2H), 1.43-2.22 (m, 21H), 2.59 (d, J=7.1 Hz,2H), 7.25 (d, J=7.9 Hz, 2H), 8.04 (d, J=7.9 Hz, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.49, 26.88, 29.92, 34.08, 34.79, 36.39, 36.80, 38.00, 42.95,108.74, 111.31, 126.98, 129.23, 130.24, 147.48, 171.61. Anal. Calcd forC₂₄H₃₀O₅: C, 72.34; H, 7.59. Found: C, 72.16; H, 7.37.

[0229]cis-Adamantane-2-spiro-3′-8′-phthalimidoethyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ215). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol)and 4-phthalimidoethylcyclohexanone (1.35 g, 5 mmol) in cyclohexane (85ml) and CH₂Cl₂ (15 ml) was treated with ozone according to the generalprocedure. The crude product was purified by flash chromatography(silica gel, 15% ether in hexanes) and by subsequent crystallizationfrom ethanol to afford trioxolane OZ215 (1.33 g, 61%) as a colorlesssolid. mp 136-138° C. (ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.43 (m,3H), 1.49-2.21 (m, 22H), 3.70 (d, J=7.5 Hz, 2H), 7.62-7.78 (m, 2H),7.79-7.97 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.48, 26.87, 29.81,33.78, 34.04, 34.76, 34.79, 36.05, 36.38, 36.80, 108.73, 111.18, 123.14,132.16, 133.84, 168.33. Anal. Calcd for C₂₆H₃₁NO₅: C, 71.37; H, 7.14; N,3.20. Found: C, 71.50; H, 6.93; N, 3.16.

[0230]Adamantane-2-spiro-3′-8′-(4′-pyridinylmethyl)-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ216). To a stirred solution of OZ80 (200 mg, 0.66 mmol) in1,2-dichloroethane (5 ml) at rt was added triethylamine (0.2 ml, 1.2mmol) followed by 4-pyridinecarboxaldehyde (71 mg, 0.66 mmol) and sodiumtriacetoxyborohydride (197 mg, 0.924 mmol). The resulting mixture wasstirred at rt for 2 h, quenched with saturated aqueous NaHCO₃ (5 ml),and extracted with EtOAc (3×10 ml). The combined organic extracts weredried over MgSO₄, filtered, and concentrated. Crystallization of thecrude product from ether/methanol (3:1) gave trioxolane OZ216 (167 mg,71%) as a colorless solid. mp 124-126° C. (ether/methanol 3:1); ¹H NMR(500 MHz, CDCl₃). 1.59-2.19 (m, 18H), 2.37-2.51 (m, 4H), 3.52 (s, 2H),7.27 (d, J=4.9 Hz, 2H), 8.54 (d, J=5.0 Hz, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.45, 26.87, 34.45, 34.74, 34.83, 36.40, 36.75, 51.24, 61.20,106.94, 111.70, 123.63, 148.00, 149.81. Anal. Calcd for C₂₁H₂₈N₂O₃: C,70.76; H, 7.92; N, 7.86. Found: C, 70.80; H, 7.77; N, 7.65.

[0231]cis-Adamantane-2-spiro-3′-8′-[[[(2′-thiazolyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ217). To a solution of OZ78 (322 mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0°C. were added triethylamine (303 mg, 3 mmol) and ethyl chloroformate(217 mg, 2 mmol). The mixture was stirred at 0° C. for 15 min before2-aminothiazole (100 mg, 1 mmol) was added. The resulting mixture wasstirred at rt for 12 h, concentrated, and triturated with water. Thecrude product was purified by crystallization from ethanol to affordtrioxolane OZ217 (0.29 g, 72%) as a colorless solid. mp 160-162° C.(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.19-1.47 (m, 2H), 1.51-2.18 (m,21H), 2.46 (d, J=6.9 Hz, 2H), 7.02 (d, J=3.6 Hz, 1H), 7.42 (d, J=3.6 Hz,1H), 12.51 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.46, 26.84, 30.10,33.23, 33.91, 34.77, 36.37, 36.77, 42.81, 108.35, 111.45, 113.68,136.10, 159.96, 170.18. Anal. Calcd for C₂₁H₂₈N₂O₄S: C, 62.35; H, 6.98;N, 6.93. Found: C, 62.28; H, 6.92; N, 6.87.

[0232]cis-Adamantane-2-spiro-3′-8′-[(1′-piperidinylcarbonyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ218). To a solution of OZ78 (322 mg, 1.0 mmol) in CH₂Cl₂ (10 ml) at0° C. were added triethylamine (202 mg, 2 mmol) and ethyl chloroformate(217 mg, 2 mmol). The mixture was stirred at 0° C. for 15 min beforepiperidine (100 mg, 1.2 mmol) was added. The resulting mixture wasstirred at rt for 12 h, concentrated, and triturated with water. Thecrude product was purified by crystallization from ethanol to affordtrioxolane OZ218 (0.24 g, 62%) as a colorless solid. mp 98-100° C.(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.39 (m, 2H), 1.43-2.17 (m,27H), 2.21 (d, J=6.8 Hz, 2H), 3.30-3.49 (m, 2H), 3.50-3.65 (m, 2H); ¹³CNMR (125.7 MHz, CDCl₃).24.57, 25.66, 26.49, 26.60, 26.87, 30.31, 33.43,34.11, 34.79, 36.39, 36.81, 39.26, 42.69, 46.87, 108.72, 111.29, 170.28.Anal. Calcd for C₂₃H₃₅NO₄: C, 70.92; H, 9.06; N, 3.60. Found: C, 70.83;H, 8.99; N, 3.60.

[0233] cis-Adamantane-2-spiro-3′-8′-(1′H-imidazol-1′-ylethyl)-1′,2′,4′-trioxaspiro[4.5]decane (OZ219). Step 1.To a solution of OZ89 (924 mg, 3 mmol) and triethylamine (606 mg, 6mmol) in CH₂Cl₂ (30 ml) at 0° C. was added methanesulfonyl chloride (516mg, 4.5 mmol). The mixture was stirred at rt for 1 h, diluted withCH₂Cl₂ (20 ml), and washed with with water (2×10 ml) and brine (10 ml).The organic layer was dried over MgSO₄, filtered, and concentrated toafford the methanesulfonate (1.16 g, 100%) as a colorless solid. Step 2.To a solution of imidazole (100 mg, 1.5 mmol) in DMF (5 ml) was added60% NaH (75 mg, 1.9 mmol). The mixture was stirred for 15 min before asolution of the above methanesulfonate (0.40 g, 1 mmol) in DMF (2 ml)was added dropwise. The mixture was heated at 50° C. for 3 h, quenchedwith water (15 ml), and then extracted with ether (3×20 ml). Thecombined extracts were dried over MgSO₄, filtered, and concentrated.Crystallization of the residue from hexanes/ether (19:1) gave trioxolaneOZ219 (0.22 g, 61%) as a colorless solid. mp 116-118° C. (hexanes/ether,19:1); ¹H NMR (500 MHz, CDCl₃) δ0 1.11-1.39 (m, 3H), 1.51-2.18 (m, 22H),3.95 (t, J=8.0 Hz, 2H), 6.89 (s, 1H), 7.06 (s, 1H), 7.46 (s, 1H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.46, 26.85, 29.80, 33.26, 33.93, 34.77,36.38, 36.77, 37.35, 44.81, 108.48, 111.40, 118.65, 129.52, 136.95.Anal. Calcd for C₂₁H₃₀N₂O₃: C, 70.36; H, 8.44; N, 7.81. Found: C, 70.14;H, 8.27; N, 7.81.

[0234]Adamantane-2-spiro-3′-8′-benzyl-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane(OZ220). To a stirred solution of OZ80 (200 mg, 0.66 mmol) in1,2-dichloroethane (5 ml) at rt was added triethylamine (0.2 ml, 1.2mmol) followed by benzaldehyde (70 mg, 0.66 mmol) and sodiumtriacetoxyborohydride (197 mg, 0.924 mmol). The resulting mixture wasstirred at rt for 2 h, quenched with saturated aqueous NaHCO₃ (5 ml),and extracted with EtOAc (3×10 ml). The combined organic extracts weredried over MgSO₄, filtered, and concentrated. Crystallization of thecrude product from ether/methanol (3:1) gave trioxolane OZ220 (177 mg,75%) as a colorless solid. mp 108-110° C. (ether/methanol 3:1); ¹H NMR(500 MHz, CDCl₃) δ 1.58-2.21 (m, 18H), 2.38-2.52 (m, 2H), 2.53-2.69 (m,2H), 3.51 (s, 2H), 7.18-7.45 (m, 5H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.47, 26.88, 34.46, 34.75, 34.83, 36.40, 36.78, 51.09, 62.50, 107.26,111.56, 126.99, 128.21, 128.96, 138.63. Anal. Calcd for C₂₂H₂₉NO₃: C,74.33; H, 8.22; N, 3.94. Found: C, 74.52; H, 8.17; N, 4.03.

[0235]cis-Adamantane-2-spiro-3′-8′-[(aminocarbonyl)amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ221). To a solution of OZ137 (550 mg, 1.74 mmol) in CH₂Cl₂ (10 ml) atrt were added pyridine (1.38 g, 17.4 mmol), acetic acid (1.01 g, 16.8mmol), triethylamine (349 mg, 3.45 mmol), and KOCN (278 mg, 3.45 mmol).The resulting mixture was stirred at rt for 48 h, diluted with ether(100 ml), and washed with water (100 ml) and brine (25 ml). The organiclayer was separated, dried over MgSO₄, and concentrated to givetrioxolane OZ221 (166 mg, 30%) as a colorless solid. mp 140-142° C.(ether); ¹H NMR (500 MHz, CDCl₃) δ 1.35-1.52 (m, 2H), 1.62-2.21 (m,20H), 3.51-3.54 (m, 1H), 4.70 (s, 2H), 4.58-5.03 (m, 1H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.43, 26.80, 30.34, 32.61, 34.76, 36.30, 36.73, 47.41,107.88, 111.66, 158.32. Anal. Calcd for C₁₇H₂₆N₂O₄: C, 63.33; H, 8.13;N, 8.69. Found: C, 63.06; H, 8.29; N, 8.49.

[0236]cis-Adamantane-2-spiro-3′-8′-[[(tert-butylamino)carbonyl]amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ222). To a solution of OZ137 (315 mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0°C. were added triethylamine (350 mg, 3.48 mmol) and tert-butylisocyanate (100 mg, 1 mmol). The resulting mixture was stirred at rt for7 h before removal of solvents. The residue was triturated with water(10 ml) and further purified by crystallization from 95% ethanol to givetrioxolane OZ222 (300 mg, 79%) as a colorless solid. mp 130° C. dec(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.32 (s, 9H), 1.22-2.21 (m, 22H),3.64 (s, 1H), 4.28 (s, 1H), 4.37 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.44, 26.81, 29.54, 30.64, 32.83, 34.75, 36.30, 36.74, 47.05, 50.29,108.01, 111.53. Anal. Calcd for C₂₁H₃₄N₂O₄: C, 66.64; H, 9.05; N, 7.40.Found: C, 66.65; H, 9.01; N, 7.22.

[0237]cis-Adamantane-2-spiro-3′-8′-(5′-methoxycarbonyl-1′H-imidazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ223). To a suspension of 60% NaH (0.24 g, 6 mmol) in DMF (5 ml) undernitrogen at 0° C. was added a solution of methyl 4-imidazolecarboxylate(0.76 g, 6 mmol) in DMF (18 ml). The mixture was stirred for 30 minbefore a solution of the methanesulfonate of OZ119 (0.96 g, 2.6 mmol) inDMF (6 ml) was added dropwise. The reaction mixture was heated at 55° C.overnight, quenched with water (100 ml), and then extracted with CH₂Cl₂(3×50 ml). The combined extracts were washed with water and brine, driedover MgSO₄, filtered, and concentrated. The crude product was purifiedby flash chromatography (silica gel, 40% ethyl acetate in hexanes, then5% methanol in CH₂Cl₂) to afford trioxolane OZ223 (0.21 g, 20%, elutedfirst) as a colorless solid and trioxolane OZ224 (0.36 g, 47%, elutedsecond) as a colorless solid. For OZ223: mp 148-150° C. (hexanes/CH₂Cl₂,4:1); ¹H NMR (500 MHz, CDCl₃) δ 51.17-1.41 (m, 2H), 1.55-2.18 (m, 21H),3.85 (s, 3H), 4.13 (d, J=7.0 Hz, 2H), 7.52 (s, 1H), 7.75 (s, 1H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.43, 26.83, 27.43, 33.45, 34.74, 36.34,36.74, 36.96, 51.43, 52.08, 108.33, 111.48, 122.20, 138.15, 142.54,160.70. Anal. Calcd for C₂₂H₃₀N₂O₅: C, 65.65; H, 7.51; N, 6.96. Found:C, 65.78; H, 7.41; N, 6.97.

[0238]cis-Adamantane-2-spiro-3′-8′-(4′-methoxycarbonyl-1′H-imidazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ224). For the preparation of OZ224, see OZ223. mp 150-152° C.(ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.39 (m, 2H), 1.49-2.15 (m,21H), 3.81 (d, J=7.4 Hz, 2H), 3.89 (s, 3H), 7.44 (s, 1H), 7.57 (s, 1H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.42, 26.81, 27.53, 33.39, 34.75, 36.34,36.72, 37.73, 51.66, 52.95, 108.01, 111.68, 125.29, 133.99, 138.15,163.25. Anal. Calcd for C₂₂H₃₀N₂O₅: C, 65.65; H, 7.51; N, 6.96. Found:C, 65.79; H, 7.34; N, 6.85.

[0239] cis-Adamantane-2-spiro-3′-8′-(4′-carboxy-1′H-imidazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane (OZ225). Amixture of OZ224 (0.16 g, 0.4 mmol), 15% KOH (1.5 ml), and methanol (15ml) was heated at 55° C. for 4 h. After being cooled to rt, the mixturewas concentrated to 3 ml, diluted with water (15 ml), and acidified withacetic acid to pH=5. The solid was collected by filtration to affordtrioxolane OZ225 (0.10 g, 64%) as a colorless solid. mp 162° C. dec; ¹HNMR (500 MHz, DMSO-d₆) δ 1.01-1.23 (m, 2H), 1.40-2.05 (m, 21H), 3.87 (d,J=7.3 Hz, 2H), 7.64 (s, 1H), 7.71 (s, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆)δ 25.96, 26.37, 27.05, 33.03, 34.42, 35.90, 36.25, 36.66, 51.32, 108.54,110.75, 125.80, 134.59, 138.63, 164.23. Anal. Calcd for C₂₁H₂₈N₂O_(O)₅H₂O: C, 62.05; H, 7.44; N, 6.89. Found: C, 62.36; H, 7.16; N, 6.50.

[0240]Adamantane-2-spiro-3′-8′-phenyl-1′,2′,4′-trioxaspiro[4.5]dec-7′-ene(OZ226). Step 1. Addition of phenyllithium to OZ05. To a stirredsolution of OZ05 (1.10 g, 4.0 mmol) in ether (50 ml) at −78° C. wasadded phenyllithium (2.6 ml, 1.8 M, 4.40 mmol). The reaction mixture wasallowed to reach rt during 3 h and quenched with saturated aq. NH₄Clsolution (30 ml). After the ether layer was separated, the aqueous layerwas extracted with ether (3×40 ml). The combined organic extracts werewashed with brine (50 ml), dried over MgSO₄, and concentrated. The crudeproduct was purified by flash chromatography (silica gel, 5% EtOAc inhexanes) to afford the trioxolane carbinol intermediate (923 mg, 65%,1:1 mixture of two diastereomers) as a colorless oil. ¹H NMR (500 MHz,CDCl₃) δ 1.58-2.39 (m, 22H), 7.19-7.28 (m, 1H), 7.29-7.40 (m, 2H),7.42-7.55 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.64, 26.66, 27.06,27.08, 30.36, 30.46, 34.84, 34.90, 34.91, 35.10, 36.45, 36.51, 36.57,36.63, 36.92, 36.95, 72.08, 72.38, 108.39, 108.41, 111.52, 111.64,124.41, 124.57, 126.98, 127.07, 128.32, 128.35, 148.11, 148.30. Step 2.Dehydration of the carbinol intermediate. To a stirred solution of theabove carbinol (550 mg, 1.54 mmol) in CH₂Cl₂ (10 ml) at −10° C. wasadded triethylamine (1.0 ml, 7.75 mmol) followed by a solution ofmethanesulfonyl chloride (0.25 ml, 3.10 mmol) in CH₂Cl₂ (5 ml). Theresulting mixture was stirred at 0° C. for 8 h and poured into water (10ml). After separation of the organic layer, the aqueous layer wasextracted with CH₂Cl₂ (3×15 ml). The combined organic extracts weredried over MgSO₄, filtered, and concentrated. The crude product waspurified by flash chromatography (silica gel, 1% ether in hexanes) andby subsequent recrystallization from ether/hexanes (1:1) to affordtrioxolane OZ226 (435 mg, 83%) as a colorless solid. mp 62-64° C.(ether/hexanes, 1:1); ¹H NMR (500 MHz, CDCl₃) δ 1.42-2.21 (m, 16H),2.40-2.73 (m, 4H), 5.73-5.99 (m, 1H), 7.02-7.45 (m, 5H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.54, 26.71, 27.10, 31.36, 34.81, 34.88, 34.95, 35.12,35.23, 36.64, 36.70, 36.98, 107.80, 111.81, 120.95, 125.27, 126.96,128.25, 136.69, 141.52. Anal. Calcd for C₂₂H₂₆O₃: C, 78.07; H, 7.74.Found: C, 78.28; H, 7.81.

[0241]cis-Adamantane-2-spiro-3′-8′-[[(4′-methyl-1′-piperazinyl)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ227). To a solution of OZ78 (322 mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0°C. were added triethylamine (303 mg, 3 mmol) and ethyl chloroformate(217 mg, 2 mmol). The mixture was stirred at 0° C. for 15 min before1-methylpiperazine (110 mg, 1.1 mmol) was added. The resulting mixturewas stirred at rt for 12 h, diluted with CH₂Cl₂ (10 ml), washed withwater (10 ml), dried over MgSO₄, and concentrated. The crude product waspurified by crystallization from ethanol to afford trioxolane OZ227(0.19 g, 47%) as a colorless solid. mp 96-98° C. (ethanol); ¹H NMR (500MHz, CDCl₃) δ 1.15-1.37 (m, 2H), 1.59-2.18 (m, 21H), 2.21 (d, J=6.9 Hz,2H), 2.29 (s, 3H), 2.30-2.58 (m, 4H), 3.40-3.57 (m, 2H), 3.58-3.78 (m,2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.64, 27.02, 30.34, 33.41, 34.13,34.87, 36.56, 36.93, 39.18, 41.62, 45.75, 45.94, 54.89, 55.31, 108.66,111.32, 170.46. Anal. Calcd for C₂₃H₃₆N₂O₄: C, 68.29; H, 8.97; N, 6.92.Found: C, 68.07; H, 8.69; N, 6.81.

[0242]cis-Adamantane-2-spiro-3′-8′-(azidoethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ228). For the preparation of the mesylate of OZ89, see OZ219. To asolution of NaN₃ (375 mg, 5 mmol) in DMF (5 ml) was added the mesylate(760 mg, 2 mmol) in DMF (2 ml). The mixture was stirred at 50-55° C. for16 h before being quenched with water (15 ml). After separation of theorganic layer, the aqueous layer was extracted with ether (3×20 ml). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. The residue was purified by crystallization from ethanolto give trioxolane OZ228 (618 mg, 93%) as a colorless solid. mp 58-60°C. (ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.11-1.37 (m, 2H), 1.38-1.48 (m,1H), 1.49-1.61 (m, 2H), 1.62-2.18 (m, 20H), 3.29 (t, J=7.0 Hz, 2H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.69, 27.10, 29.91, 33.63, 34.13, 34.92,34.94, 35.02, 36.62, 36.99, 49.44, 108.69, 111.37. Anal. Calcd forC₁₈H₂₇N₃O₃: C, 64.84; H, 8.16; N, 12.60. Found: C, 64.68; H, 7.94; N,12.47.

[0243]cis-Adamantane-2-spiro-3′-8′-(aminoethyl)-1′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ229). To a solution of OZ228 (333 mg, 1 mmol) in THF (7ml) were added triphenylphosphine (262 mg, 1 mol) and water (1 ml). Themixture was stirred at rt for 16 h and diluted with 2 M aq. HCl (5 ml).The precipitate was filtered, and washed with CH₂Cl₂ (10 ml), and driedto give trioxolane OZ229 (194 mg, 56%) as a colorless solid. mp 150-152°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 1.00-1.19 (m, 2H), 1.25-2.08 (m, 23H),2.67-2.89 (m, 2H), 8.04 (s, 3H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.83,26.23, 29.33, 32.40, 33.02, 33.37, 34.24, 34.26, 35.81, 36.11, 36.81,108.36, 110.45. Anal. Calcd for C₁₈H₃₀ClNO₃: C, 62.87; H, 8.79; N, 4.07.Found: C, 63.00; H, 8.58; N, 4.34.

[0244]N,N′-Bis[cis-[adamantane-2-spiro-3′-1′,2′,4′-trioxaspiro[4.5]dec-8′-yl]methyl]-1,2-benzenedicarboxamide(OZ230). A solution of OZ146 (10.40 g, 24.60 mmol) and hydrazinemonohydrate (5.00 g, 50 mmol) in chloroform (180 ml) and methanol (20ml) was heated under nitrogen at 55° C. for 24 h. The reaction mixturewas cooled to rt and filtered to remove solid by-products. The filtratewas washed with water (100 ml) and brine (100 ml), dried over MgSO₄,filtered, and concentrated. The crude product was purified by flashchromatography (silica gel, CHCl₃/MeOH/Et₃N, 90:10:1) to affordtrioxolane OZ230 (1.60 g, 20%, eluted first) andcis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decane(5.10 g, 71%, eluted second). OZ230 was obtained as a colorless solid.mp 164-166° C. (CHCl₃/ethanol 9:1); ¹H NMR (500 MHz, CDCl₃) δ 1.19-1.39(m, 4H), 1.59-2.11 (m, 42H), 3.19-3.35 (m, 4H), 6.75-6.88 (m, 2H),7.41-7.52 (m, 2H), 7.53-7.65 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.48, 26.88, 27.81, 33.77, 34.79, 36.29, 36.39, 36.80, 45.39, 108.54,111.38, 128.51, 130.27, 134.51, 169.27. Anal. Calcd for C₄₂H₅₆N₂O₈: C,70.37; H, 7.87; N, 3.91. Found: C, 70.50; H, 7.81; N, 3.99.

[0245]cis-Adamantane-2-spiro-3′-8′-(5′-carboxy-1′H-imidazol-1′-ylmethyl)-1′,2′,4′-30trioxaspiro[4.5]decane (OZ231). A mixture of OZ223 (0.10 g, 0.25 mmol),15% KOH (1.0 ml), methanol (10 ml), and THF (2 ml) was heated at 55° C.for 4 h. After being cooled to room temperature, the mixture wasconcentrated to 3 ml, diluted with water (15 ml), and acidified withacetic acid to pH=5. The solid was collected by filtration to affordtrioxolane OZ231 (77 mg, 79%) as a colorless solid. mp 164-166° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 1.03-1.37 (m, 2H), 1.38-2.18 (m, 21H), 4.16 (d,J=6.7 Hz, 2H), 7.58 (s, 1H), 7.89 (s, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆)δ 25.86, 26.26, 26.88, 32.92, 34.29, 35.81, 36.14, 36.44, 50.38, 108.39,110.62, 122.87 (br s), 137.04 (br s), 143.25 (br s), 161.10. Anal. Calcdfor C₂₁H₂₈N₂O₅.0.5H₂O: C, 63.46; H, 7.35; N, 7.05. Found: C, 63.41; H,7.11; N, 6.71.

[0246]cis-Adamantane-2-spiro-3′-8′-[(dimethylamino)methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ232). A solution ofcis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decane(293 mg, 1 mmol), formaldehyde (162 mg, 37% aq. solution, 2 mmol),sodium triacetoxyborohydride (612 mg, 2.8 mmol) in 1,2-dichloroethane(15 ml) was stirred at rt for 4 h before being quenched with saturatedaq. NaHCO₃ (10 ml). After separation of the organic layer, the aqueouslayer was extracted with CH₂Cl₂ (2×20 ml). The combined organic layerswere washed with water and brine, dried over MgSO₄, and concentrated.The resulting crude product was dissolved in CH₂Cl₂/ether (1:5, 10 ml)and treated with a solution of methanesulfonic acid (96 mg, 1 mmol) inether (2 ml). The precipitate was collected by filtration to affordtrioxolane OZ232 (230 mg, 55%) as a colorless solid. mp 130° C. dec; ¹HNMR (500 MHz, DMSO-d₆) δ 1.25-1.45 (m, 2H), 1.59-2.16 (m, 21H), 2.82 (s,3H), 2.87 (app t, J=6.2 Hz, 2H), 2.91 (app d, J=4.6 Hz, 6H), 10.61 (s,1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 26.57, 26.96, 28.20, 32.46, 33.37,34.84, 36.50, 36.85, 39.25, 44.35, 64.04, 107.55, 111.77. Anal. Calcdfor C₂₀H₃₅NO₆S.0.6H₂O: C, 55.92; H, 8.53; N, 3.26. Found: C, 55.71; H,8.08; N, 3.12.

[0247]cis-Adamantane-2-spiro-3′-8′-(5′-methoxycarbonyl-1′H-1′,2′,4′-triazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ233). To a suspension of 60% NaH (0.20 g, 5 mmol) in DMF (5 ml) undernitrogen at 0° C. was added a solution of methyl1H-1,2,4-triazole-3-carboxylate (0.64 g, 5 mmol) in DMF (5 ml). Themixture was stirred for 1 h before a solution of the methanesulfonate ofOZ119 (0.93 g, 2.5 mmol) in DMF (5 ml) was added dropwise. The reactionmixture was heated at 55° C. overnight, quenched with water (60 ml), andthen extracted with CH₂Cl₂ (3×40 ml). The combined extracts were washedwith water and brine, dried over MgSO₄, filtered, and concentrated. Thecrude product was purified by flash chromatography (silica gel, 33% to66% ethyl acetate in hexanes) to afford trioxolane OZ233 (0.27 g, 27%,eluted first) as a colorless solid and trioxolane OZ234 (0.21 g, 21%,eluted second) as a colorless solid. For OZ233: mp 120-122° C.; ¹H NMR(500 MHz, CDCl₃) δ 1.29-1.49 (m, 2H), 1.52-2.16 (m, 21H), 3.99 (s, 3H),4.50 (d, J=7.1 Hz, 2H), 7.96 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.64, 27.04, 27.46, 33.59, 34.89, 36.57, 36.94, 37.15, 52.90, 55.75,108.32, 111.53, 150.78, 158.49, 181.90. Anal. Calcd for C₂₁H₂₉N₃O₅: C,62.51; H, 7.24; N, 10.41. Found: C, 62.40; H, 7.11; N, 10.51.

[0248]cis-Adamantane-2-spiro-3′-8′-(3′-methoxycarbonyl-1′H-1′,2′,4′-triazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ234). For the preparation of OZ234, see OZ233. mp 144-146° C.; ¹H NMR(500 MHz, CDCl₃) δ 1.23-1.41 (m, 2H), 1.52-2.16 (m, 21H), 3.99 (s, 3H),4.07 (d, J=7.2 Hz, 2H), 8.08 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.61, 27.00, 27.55, 33.45, 34.87, 36.50, 36.55, 36.89, 52.55, 55.73,108.07, 111.70, 144.75, 155.30, 160.13. Anal. Calcd for C₂₁H₂₉N₃O₅: C,62.51; H, 7.24; N, 10.41. Found: C, 62.62; H, 7.17; N, 10.52.

[0249]cis-Adamantane-2-spiro-3′-8′-(1′H-1′,2′,4′-triazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ235). To a solution of OZ177 (1.20 g, 3.5 mmol) in ether (10ml) was added a solution of methanesulfonic acid (0.40 g, 4.2 mmol) inether (10 ml). The resulting mixture was placed at −20° C. overnight.The solid was collected by filtration and dried in vaccuo to affordtrioxolane OZ235 (1.48 g, 96%) as a colorless solid. mp 139-142° C.; ¹HNMR (500 MHz, CDCl₃) δ 1.26-1.44 (m, 2H), 1.58-2.19 (m, 21H), 2.86 (s,3H), 4.33 (d, J=7.1 Hz, 2H), 8.54 (s, 1H), 10.04 (s, 1H), 12.85 (br s,1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.58, 26.97, 27.29, 33.34, 34.85,36.21, 36.51, 36.86, 39.65, 56.71, 107.92, 111.69, 142.30, 144.05. Anal.Calcd for C₂₀H₃₁N₃O₆S: C, 54.40; H, 7.08; N, 9.52. Found: C, 54.28; H,6.92; N, 9.33.

[0250]cis-Adamantane-2-spiro-3′-8′-[[bis(2′-amino-2′-oxoethyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ236). A mixture ofcis-adamantane-2-spiro-3′-8′-aminomethyl-1′,2′,4′-trioxaspiro[4.5]decane(293 mg, 1 mmol), 2-bromoacetamide (138 mg, 1 mmol), and potassiumcarbonate (276 mg, 2 mmol) in acetonitrile (18 ml) was heated at 50° C.for 16 h before being diluted with water (25 ml). The resulting mixturewas extracted with chloroform (3×18 ml). The combined extracts werewashed with water and brine, dried over MgSO₄, and concentrated. Thecrude product was purified by falsh chromatography (silica gel, 18%methanol in CH₂Cl₂) and by recrystallization from CHCl₃ to affordtrioxolane OZ236 (180 mg, 44%) as a colorless solid. mp 157-159° C.(CHCl₃); ¹-H NMR (500 MHz, DMSO-d₆) δ 0.89-1.16 (m, 2H), 1.38-2.09 (m,21H), 2.25 (d, J=7.1 Hz, 2H), 2.97 (s, 4H), 7.13 (s, 2H), 7.50 (s, 2H);¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.96, 26.36, 28.13, 33.51, 33.54, 34.40,34.42, 35.92, 36.25, 59.21, 61.26, 108.90, 110.57, 172.79. Anal. Calcdfor C₂₁H₃₃N₃O₅: C, 61.90; H, 8.16; N, 10.31. Found: C, 62.04; H, 7.91;N, 10.12.

[0251]cis-Adamantane-2-spiro-3′-8′-[[(aminoiminomethyl)amino]methyl]-11′,2′,4′-trioxaspiro[4.5]decanehydrochloride (OZ237). A mixture ofcis-adamantane-2-spiro-3′-8′-aminomethyl-1′,2′,4′-trioxaspiro[4.5]decane(293 mg, 1 mmol), 1H-pyrazole-1-carboxamidine hydrochloride (147 mg, 1mmol), N,N-diisopropylethylamine (129 mg, 1 mmol) in DMF (5 ml) wasstirred at rt for 16 h before being diluted with ether (50 ml). Thesolid was collected by filtration and recrystallized from 30% aq.ethanol to afford trioxolane OZ237 (210 mg, 56%) as a colorless solid.mp 146-149° C. (30% aq. ethanol); ¹-H NMR (500 MHz, DMSO-d₆) δ 0.99-1.21(m, 2H), 1.39-2.05 (m, 21H), 2.98 (app t, J=6.0 Hz, 2H), 6.50-7.89 (m,5H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.86, 26.27, 27.00, 33.05, 34.31,35.28, 35.83, 36.14, 45.59, 108.41, 110.61, 157.17. Anal. Calcd forC₁₈H₃₀ClN₃O₃: C, 58.13; H, 8.13; N, 11.30. Found: C, 58.31; H, 8.27; N,10.96.

[0252]cis-Adamantane-2-spiro-3′-8′-(2′-amino-2′-oxoethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ243). To a solution of OZ78 (322 mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0°C. was added TEA (202 mg, 2 mmol) followed by ethyl chloroformate (217mg, 2 mmol). After 15 min, ammonia (7 N in methanol, 3 ml) was added,and the stirring was continued for 12 h. The precipitate was filteredand dried to afford trioxolane OZ243 (210 mg, 65%) as a colorless solid.mp 140-142° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.09-1.43 (m, 3H), 1.45-2.15(m, 20H), 2.11 (d, J=7.1 Hz, 2H), 5.48 (s, 1H), 5.66 (s, 1H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.47, 26.85, 29.97, 33.32, 33.95, 34.77, 36.38,36.78, 42.55, 108.50, 111.35, 174.39. Anal. Calcd for C₁₈H₂₇NO₄: C,67.26; H, 8.47; N, 4.36. Found: C, 67.40; H, 8.47; N, 4.39.

[0253]cis-Adamantane-2-spiro-3′-8′-[[(4′-phenyl-1′-piperazinyl)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ244). To a solution of OZ78 (322 mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0°C. was added TEA (202 mg, 2 mmol) followed by ethyl chloroformate (217mg, 2 mmol). After 15 min, 1-phenylpiperazine (162 mg, 1 mmol) wasadded, and the stirring was continued for 12 h. The reaction mixture wasconcentrated, diluted with water, and filtered. The crude product waspurified by recrystallization from ethanol to give trioxolane OZ244 (280mg, 60%) as a colorless solid. mp 140-142° C. (ethanol); ¹H NMR (500MHz, CDCl₃) δ 1.18-1.38 (m, 2H), 1.55-2.18 (m, 21H), 2.26 (d, J=6.9 Hz,2H), 3.02-3.29 (m, 4H), 3.55-3.70 (m, 2H), 3.71-3.89 (m, 2H), 6.81-7.02(m, 3H), 7.20-7.38 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.48, 26.86,30.30, 33.34, 34.06, 34.78, 36.39, 36.79, 39.18, 41.51, 45.69, 49.47,49.77, 108.59, 111.33, 116.58, 120.51, 129.22, 150.91, 170.50. Anal.Calcd for C₂₈H₃₈N₂O₄: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.22; H,8.16; N, 5.99.

[0254]Adamantane-2-spiro-3′-8′-hydroxy-8′-(2′-thiazolyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ247). To a stirred solution of 2-bromothiazole (246 mg, 1.5 mmol) indry THF (4 ml) under N₂ at −78° C. was added n-BuLi (1.6 M in hexanes, 1ml, 1.5 mmol). The resulting bright yellow solution was stirred for 1 hat the same temperature, and then a solution of OZ05 (415 mg, 1.5 mmol)in dry THF (10 ml) was added. The mixture was allowed to reach 0° C.,poured into ice-water mixture (15 ml), and extracted with ether (3×25ml). The combined organic extracts were washed with brine (25 ml), driedover MgSO₄, and concentrated. The crude product was purified by flashchromatography (silica gel, 10% EtOAc in hexanes) followed byrecrystallization from hexanes/ether (9:1) to afford trioxolane OZ247(202 mg, 37%, 1:1 mixture of 2 diastereomers) as a colorless solid. mp64-66° C. (hexanes/ether 9:1); ¹H NMR (500 MHz, CDCl₃).1.60-2.42 (m,22H), 3.18 (s, 0.5H), 3.40 (s, 0.5H), 7.28 (d, J=3.0 Hz, 0.5H), 7.30 (d,J=3.0 Hz, 0.5H), 7.69 (d, J=3.3 Hz, 0.5H), 7.72 (d, J=3.0 Hz, 0.5H); ¹CNMR (125.7 MHz, CDCl₃) δ 26.45, 26.46, 26.85, 29.98, 30.09, 34.73,34.77, 34.79, 34.86, 36.34, 36.40, 36.48, 36.75, 36.77, 72.44, 73.00,107.91, 107.97, 111.61, 111.84, 119.02, 141.95, 142.16, 177.99, 178.23.Anal. Calcd for C₁₉H₂₅NO₄S: C, 62.78; H, 6.93; N, 3.85. Found: C, 62.94;H, 7.01; N, 3.89.

[0255]cis-Adamantane-2-spiro-3′-8′-(1′H-imidazol-2′-yl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ251). Step 1. To a solution of oxalyl chloride (0.99 g, 7.8 mmol) inCH₂Cl₂ (50 ml) at −78° C. was added methyl sulfoxide (1.41 g, 18 mmol)dropwise. The mixture was stirred at −78° C. for 30 min before OZ119(1.76 g, 6 mmol) in CH₂Cl₂ (5 ml) was added. After the resulting mixturewas stirred for 45 min, triethylamine (3.03 g, 30 mmol) was added. Themixture was warmed to rt for 2 h and quenched with water (50 ml). Theorganic layer was washed with water (2×30 ml) and brine, dried overMgSO₄, and concentrated. The crude product (1.80 g) was crystallizedfrom 50% ethanol to afford the desired aldehyde,cis-Adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane,(0.82 g, 47%) as a colorless solid. mp 74-76° C. (50% ethanol); ¹-H NMR(500 MHz, CDCl₃) δ 1.64-2.02 (m, 22H), 2.20-2.30 (m, 1H), 9.63 (d, J=1.1Hz, 1H). Step 2. To a solution of the above aldehyde (292 mg, 1 mmol)and 40% glyoxal (145 mg, 1 mmol) in methanol (12 ml) at 0° C. was addedammonia (0.45 ml, 7 N in methanol). The resulting mixture was stirred atrt overnight and concentrated. The crude product was crystallized fromhexanes/CH₂Cl₂ (3:2) to afford trioxolane OZ251 (240 mg, 73%) as acolorless solid. mp 138-140° C. (hexanes/CH₂Cl₂, 3:2); ¹H NMR (500 MHz,CDCl₃) δ 1.58-2.23 (m, 22H), 2.75-2.98 (m, 1H), 6.96 (s, 2H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.54, 26.94, 29.11, 33.92, 34.82, 34.86, 36.23,36.47, 36.84, 108.00, 111.54, 121.10 (br s), 151.00. Anal. Calcd forC₁₉H₂₆N₂O₃: C, 69.06; H, 7.93; N, 8.48. Found: C, 69.04; H, 7.93; N,8.60.

[0256]cis-Adamantane-2-spiro-3′-8′-[(2′-thiazolylamino)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ252). A mixture ofcis-Adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), 2-aminothiazole (150 mg, 1.5 mmol), and acetic acid (240mg, 4.0 mmol) in CH₂Cl₂ (10 ml) and ClCH₂CH₂Cl (10 ml) was stirred at rtfor 2.5 h before sodium triacetoxyborohydride (422 mg, 2.0 mmol) wasadded. The resulting mixture was stirred at rt overnight and thenquenched with saturated aq. NaHCO₃ (50 ml). The organic layer wasseparated and washed with water and brine, dried over MgSO₄, andconcentrated. The crude prude was purified by flash chromatography(silica gel, 2% CH₃OH in CH₂Cl₂). The enriched product was dissolved inether/CH₂Cl₂ (4:1, 20 ml), treated with methanesulfonic acid (40 mg, 0.4mmol), and placed at −20° C. overnight. After the solvent was decanted,the residue was washed with ether and dried in vacuo to affordtrioxolane OZ252 (110 mg, 23%) as a colorless solid. mp 136-138° C.; ¹HNMR (500 MHz, CDCl₃) δ 1.20-1.41 (m, 2H), 1.50-2.21 (m, 21H), 2.88 (s,3H), 3.11 (app t, J=6.1 Hz, 2H), 6.54 (d, J=4.1 Hz, 1H), 7.05 (d, J=4.1Hz, 1H), 10.51 (s, 1H), 14.17 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.46, 26.84, 27.88, 33.44, 34.77, 35.66, 36.38, 36.76, 39.45, 54.26,104.97, 108.18, 111.57, 127.14, 170.79. Anal. Calcd for C₂₁H₃₂N₂O₆S₂: C,53.37; H, 6.82; N, 5.93. Found: C, 53.16; H, 6.76; N, 5.91.

[0257]cis-Adamantane-2-spiro-3′-8′-[(cyclopropylamino)methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ253). To a solutioncis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), cyclopropylamine (57 mg, 1.0 mmol), and acetic acid (90mg, 1.5 mmol) in 1,2-dichloroethane (10 ml) was added sodiumtriacetoxyborohydride (295 mg, 1.4 mmol). The mixture was stirred for 2h and then quenched with saturated aq. NaHCO₃ (20 ml). The organic layerwas separated and the aqueous layer was extracted with CH₂Cl₂ (2×20 ml).The combined organic extracts were washed with water and brine, driedover MgSO₄, and concentrated. The crude product was purified by flashchromatography (silica gel, 20% ether in hexanes, 400 ml; then 10%methanol in CH₂Cl₂, 300 ml) to give two fractions. The first fraction(130 mg) was crystallized from CH₃OH/CH₂Cl₂ (6:1) to afford trioxolaneOZ254 (96 mg, 31%) as a colorless solid. The second fraction (160 mg)was dissolved in ether (3 ml) and treated with a solution ofmethanesulfonic acid (46 mg) in ether (3 ml). The precipitate wascollected by filtration and dried in vacuo to afford trioxolane OZ253(160 mg, 37%) as a colorless solid. For OZ253: mp 144-147° C. (ether);¹H NMR (500 MHz, CDCl₃) δ 0.77-0.95 (m, 2H), 1.10-1.22 (m, 2H),1.23-1.41 (m, 2H), 1.50-2.19 (m, 21H), 2.50-2.69 (m, 1H), 2.73 (s, 3H),2.82-3.02 (m, 2H), 8.63 (s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 3.70,26.46, 26.86, 27.89, 31.23, 33.10, 33.43, 34.77, 36.38, 36.77, 39.51,54.07, 107.97, 111.50. Anal. Calcd for C₂₁H₃₅NO₆S: C, 58.72; H, 8.21; N,3.26. Found: C, 58.65; H, 8.15; N, 3.35.

[0258]N,N-Bis(cis-adamantane-2-spiro-3′-1′,2′,4′-trioxaspiro[4.5]decane-8′-methyl)cyclopropylamine(OZ254). For the preparation of trioxolane OZ254, see OZ253. mp 138-140°C. (CH₃OH/CH₂Cl₂ 6:1); ¹H NMR (500 MHz, CDCl₃) δ 0.22-0.35 (m, 2H),0.36-0.48 (m, 2H), 0.97-1.15 (m, 4H), 1.45-2.15 (m, 43H), 2.28 (d, J=7.1Hz, 4H); ¹³C NMR (125.7 MHz, CDCl₃) δ 6.80, 26.52, 26.92, 28.68, 34.09,34.43, 34.80, 34.82, 36.42, 36.85, 38.74, 63.12, 109.31, 111.15. Anal.Calcd for C₃₇H₅₅NO₆: C, 72.87; H, 9.09; N, 2.30. Found: C, 72.83; H,8.95; N, 2.33.

[0259]cis-Adamantane-2-spiro-3′-8′-[[(4′-pyridinylcarbonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ255). To a solution of OZ209 (389 mg, 1.0 mmol) and triethylamine(0.6 g, 6 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added a solution ofisonicotinoyl chloride hydrochloride (267 mg, 1.5 mmol) in CH₂Cl₂ (10ml). The resulting mixture was stirred at rt overnight before beingquenched with water (20 ml). After separation of the organic phase, theaqueous layer was extracted with CH₂Cl₂ (20 ml). The combined organicextracts were washed with water and brine, dried over MgSO₄, andconcentrated. The crude product was crystallized from 40% aq. ethanol toafford trioxolane OZ255 (410 mg, 103%) as a colorless solid. mp 145-146°C. (40% aq. ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.19-1.41 (m, 2H),1.55-2.19 (m, 21H), 3.34 (app t, J=6.3 Hz, 2H), 6.36 (br s, 1H), 7.61(d, J=4.4 Hz, 2H), 8.75 (br s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.46,26.85, 27.82, 33.71, 34.78, 36.21, 36.38, 36.76, 45.41, 108.46, 111.49,120.87, 141.70, 150.57, 165.63. Anal. Calcd for C₂₃H₃₀N₂O₄: C, 69.32; H,7.59; N, 7.03. Found: C, 69.18; H, 7.43; N, 7.04.

[0260]cis-Adamantane-2-spiro-3′-8′-[[(2′-amino-2′-oxoethyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ256). A mixture of OZ209 (389 mg, 1 mmol) and triethylamine (101 mg,1 mmol) in acetonitrile (40 ml) was stirred for 15 min before2-bromoacetamide (138 mg, 1 mmol) and potassium carbonate (276 mg, 2mmol) were added. The mixture was heated at 50° C. for 16 h, thendiluted with water (25 ml), and extracted with CH₂Cl₂ (3×20 ml). Thecombined organic extracts were washed with water and brine, dried overMgSO₄, and concentrated. The crude product was purified by flashchromatography (silica gel, 6% CH₃OH in CH₂Cl₂) to afford trioxolaneOZ256 (90 mg, 26%) as a colorless solid. mp 136-138° C.; ¹H NMR (500MHz, CDCl₃) δ 1.05-1.31 (m, 2H), 1.37-2.19 (m, 22H), 2.49 (d, J=6.4 Hz,2H), 3.25 (s, 2H), 5.95 (s, 1H), 7.04 (s, 1H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.43, 26.83, 28.07, 33.86, 34.74, 34.76, 36.35, 36.52, 36.75,52.52, 55.72, 108.73, 111.31, 174.84. Anal. Calcd forC₁₉H₃₀N₂O₄.0.25H₂O: C, 63.80; H, 8.68; N, 7.83. Found: C, 63.68; H,8.25; N, 7.82.

[0261]cis-Adamantane-2-spiro-3′-8′-[[(methanesulfonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ257). To a solution of OZ209 (389 mg, 1 mmol) and triethylamine (404mg, 4 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added a solution ofmethanesulfonyl chloride (171 mg, 1.5 mmol) in CH₂Cl₂ (1.5 ml). Themixture was stirred at rt for 16 h, washed with water and brine, driedover MgSO₄, and concentrated. The crude product was purified by flashchromatography (silica gel, 5% CH₃OH in CH₂Cl₂) to afford trioxolaneOZ257 (290 mg, 78%) as a colorless solid. mp 124-126° C.; ¹H NMR (500MHz, CDCl₃) δ 1.15-1.33 (m, 2H), 1.45-2.17 (m, 21H), 2.95 (s, 3H), 2.99(app t, J=6.7 Hz, 2H), 4.31 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.47, 26.86, 27.55, 33.60, 34.78, 34.79, 36.38, 36.77, 40.36, 48.54,108.40, 111.50. Anal. Calcd for C₁₈H₂₉NO₅S: C, 58.20; H, 7.87; N, 3.77.Found: C, 58.32; H, 7.74; N, 3.83.

[0262]Adamantane-2-spiro-3′-8′-[[2′-[(7′-chloro-4′-quinolinyl)amino]ethyl]amino]-1′,2′,4′-trioxaspiro[4.5]decane(OZ258). To a stirred solution of OZ05 (75 mg, 0.27 mmol) in CH₂Cl₂ (5ml) at rt under N₂ was addedN²-(7-chloro-4-quinolinyl)-1,2-diaminoethane (176 mg, 0.34 mmol)followed by sodium triacetoxyborohydride (72 mg, 0.34 mmol). Theresulting mixture was stirred at rt for 24 h before being poured intowater (10 ml). The organic layer was separated, dried, and concentrated.Recrystallization of the crude product from ethanol afforded trioxolaneOZ258 (86 mg, 66%) as a colorless solid. mp 146-148° C. (ethanol); ¹HNMR (500 MHz, CDCl₃) δ 1.42-2.21 (m, 23H), 2.55-2.77 (m, 1H), 3.05 (t,J=5.6 Hz, 2H), 3.34 (br s, 2H), 5.90 (br s, 1H), 6.39 (d, J=5.2 Hz, 1H),7.37 (dd, J=8.8, 1.9 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.96 (d, J=1.9 Hz,1H), 8.53 (d, J=5.2 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.65, 27.08,30.17, 32.23, 34.86, 35.06, 36.60, 36.94, 42.89, 45.17, 54.43, 99.36,108.36, 111.80, 121.09, 125.40, 125.46, 128.93, 134.98, 149.20, 150.00,152.06. Anal. Calcd for C₂₇H₃₄ClN₃O₃: C, 67.00; H, 7.08; N, 8.68.

[0263] Found: C, 67.18; H, 7.12; N, 8.49.Adamantane-2-spiro-3′-8′-(3′-pyridinylamino)-1′,2′,4′-trioxaspiro[4.5]decane(OZ259). To afford trioxolane OZ259 (? mg, 83%, 1:1 mixture of 2diastereomers) as a colorless solid. mp 132-134° C. (?); ¹H NMR (500MHz, CDCl₃) δ 1.42-2.23 (m, 22H), 3.25-3.49 (m, 1H), 3.59-3.83 (m, 1H),6.82-6.90 (m, 1H), 7.02-7.12 (m, 1H), 7.90-7.96 (m, 1H), 7.98-8.04 (m,1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.40, 26.81, 26.83, 29.40, 29.86,32.16, 32.60, 34.69, 34.72, 34.76, 34.87, 36.29, 36.32, 36.71, 49.54,49.87, 107.86, 11 1.60, 111.81, 118.78, 118.85, 123.67, 136.22, 136.45,138.57, 138.61, 143.06. Anal. Calcd for C₂₁H₂₈N₂O₃: C, 70.76; H, 7.92;N, 7.86. Found: C, 70.88; H, 7.91; N, 7.84.

[0264]cis-Adamantane-2-spiro-3′-8′-[3′-(ethoxycarbonyl)propyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ260). A solution of O-methyl 2-adamantanone oxime (895 mg, 5 mmol)and 4-[3-(ethoxycarbonyl)propyl]cyclohexanone (710 mg, 3.35 mmol) incyclohexane (85 ml) and CH₂Cl₂ (15 ml) was treated with ozone accordingto the general procedure. The crude product was purified by flashchromatography (silica gel, 5% ether in petroleum ether) and bysubsequent crystallization from ethanol to afford trioxolane OZ260 (660mg, 52%) as a colorless solid. mp 52-54° C. (ethanol); ¹H NMR (500 MHz,CDCl₃) δ 1.01-1.37 (m, 5H), 1.25 (t, J=7.1 Hz, 3H), 1.47-2.21 (m, 22H),2.27 (t, J=7.6 Hz, 2H), 4.12 (q, J=7.1 Hz, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 14.24, 22.63, 26.51, 26.90, 30.01, 34.19, 34.55, 34.79, 34.81,35.66, 35.90, 36.41, 36.83, 60.18, 108.99, 111.17, 173.68. Anal. Calcdfor C₂₂H₃₄O₅: C, 69.81; H, 9.05. Found: C, 69.82; H, 8.96.

[0265]cis-Adamantane-2-spiro-3′-8′-(3′-carboxypropyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ261). To a solution of OZ260 (250 mg, 0.66 mmol) in 95% ethanol (5ml) was added 15% NaOH solution (1 ml). The mixture was stirred at 25°C. for 24 h before being concentrated and acidified with 6 M aq. HCl (3ml). The precipitate was filtered, washed with water, and crystallizedfrom ethanol to give trioxolane OZ261 (186 mg, 81%) as a colorlesssolid. mp 156-158° C. (ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.03-1.39 (m,5H), 1.45-2.20 (m, 22H), 2.27 (t, J=7.4 Hz, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 22.33, 26.50, 26.90, 29.98, 34.06, 34.17, 34.81, 35.55, 35.87,36.40, 36.83, 108.96, 111.19, 179.14. Anal. Calcd for C₂₀H₃₀O₅: C,68.54; H, 8.63. Found: C, 68.41; H, 8.49.

[0266]cis-Adamantane-2-spiro-3′-8′-[(acetylamino)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ262). To a solution of OZ209 (389 mg, 1 mmol) and triethylamine (505mg, 5 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added dropwise a solution ofacetyl chloride (140 mg, 1.9 mmol) in CH₂Cl₂ (5 ml). The mixture wasstirred at rt for 16 h, washed with water and brine, dried over MgSO₄,and concentrated. The crude product was purified by flash chromatography(silica gel, 5% CH₃OH in CH₂Cl₂) and by crytallization fromhexanes/CH₂Cl₂ (3:1) to afford trioxolane OZ262 (150 mg, 45%) as acolorless solid. mp 102° C. dec (hexanes/CH₂Cl₂, 3:1); ¹H NMR (500 MHz,CDCl₃) δ 1.15-1.37 (m, 2H), 1.41-2.09 (m, 21H), 1.98 (s, 3H), 3.11 (appt, J=6.3 Hz, 2H), 5.52 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 23.34,26.46, 26.85, 27.72, 33.73, 34.76, 34.77, 36.16, 36.37, 36.77, 44.87,108.60, 111.38, 170.03. Anal. Calcd for C₁₉H₂₉NO₄: C, 68.03; H, 8.71; N,4.18. Found: C, 68.26; H, 8.70; N, 4.18.

[0267]cis-Adamantane-2-spiro-3′-8′-[[[(1′H-imidazol-4′-yl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ263). To a solution of 4-imidazolecarboxylic acid (134 mg,1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(290 mg, 1.5 mmol), and 1-hydroxybenzotriazole (200 mg, 1.5 mmol) in DMF(40 ml) under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at r.t. for 48 h before being quenched with water (120 ml).The mixture was extracted with CH₂Cl₂ (3×40 ml). The combined organicextracts were washed with water and brine, dried over MgSO₄, andconcentrated. The crude product was dissolved in CH₂Cl₂ (10 ml) andtreated with methanesulfonic acid (90 mg). The solid was collected byfiltration and recrytallized from ether/CH₂Cl₂/CH₃OH (3:1:1) to affordtrioxolane OZ263 (72 mg, 15%) as a colorless solid. mp 161-162° C.(ether/CH₂Cl₂/CH₃OH 3:1:1); ¹H NMR (500 MHz, DMSO-d₆) δ 1.02-1.23 (m,2H), 1.45-2.09 (m, 21H), 2.32 (s, 3H), 3.13 (app t, J=6.3 Hz, 2H), 8.12(s, 1H), 8.73 (br s, 1H), 9.03 (s, 1H), 14.47 (br s, 2H); ¹³C NMR (125.7MHz, DMSO-d₆) δ 25.96, 26.36, 27.64, 33.34, 34.41, 35.77, 35.90,36.23,44.06, 108.68, 110.66, 119.91, 120.22, 128.13, 128.22, 135.92, 136.09,157.40. Anal. Calcd for C₂₂H₃₃N₃O₇S: C, 54.64; H, 6.88; N, 8.69. Found:C, 54.72; H, 6.76; N, 8.90.

[0268]cis-Adamantane-2-spiro-3′-8′-[[[(1′-oxido-4′-pyridinyl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ264). To a solution of isonicotinic acid N-oxide (167 mg, 1.2 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (290 mg, 1.5mmol), and 1-hydroxybenzotriazole (200 mg, 1.5 mmol) in DMF (10 ml)under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at rt for 16 h before being quenched with water (50 ml). Theprecipitate was collected by filtration to afford trioxolane OZ264 (340mg, 82%) as a colorless solid. mp 152-154° C.; ¹H NMR (500 MHz, CDCl₃) δ1.21-1.43 (m, 2H), 1.49-2.11 (m, 21H), 3.33 (app t, J=6.2 Hz, 2H), 6.54(br s, 1H), 7.69 (d, J=6.3 Hz, 2H), 8.20 (d, J=6.0 Hz, 2H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.44, 26.84, 27.82, 33.69, 34.77, 36.18, 36.37,36.75, 45.56,108.43,111.52, 124.32, 131.08,139.29,163.52. Anal. Calcdfor C₂₃H₃₀N₂O₅: C, 66.65; H, 7.30; N, 6.76. Found: C, 66.81; H, 7.18; N,6.55.

[0269]cis-Adamantane-2-spiro-3′-8′-[[(aminocarbonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ265). A mixture of OZ209 (389 mg, 1 mmol), pyridine (790 mg, 10mmol), acetic acid (600 mg, 10 mmol), triethylamine (303 mg, 3 mmol),and potassium cyanate (164 mg, 2 mmol) in CH₂Cl₂ (10 ml) was stirred atr.t. for 38 h. The mixture was then washed with water and brine, driedover MgSO₄, and concentrated. The crude product was recrytallized from40% aq. ethanol to afford trioxolane OZ265 (250 mg, 74%) as a colorlesssolid. mp 138-140° C. (40% aq. ethanol); ¹H NMR (500 MHz, CDCl₃) δ1.11-1.33 (m, 2H), 1.41-2.18 (m, 21H), 3.02 (app t, J=5.5 Hz, 2H), 4.64(br s, 2H), 5.09 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.45, 26.84,27.66, 33.75, 34.76, 36.36, 36.65, 36.76, 45.85 (br s), 108.69, 111.35,158.96. Anal. Calcd for C₁₈H₂₈N₂O₄: C, 64.26; H, 8.39; N, 8.33. Found:C, 64.40; H, 8.15; N, 8.46.

[0270]cis-Adamantane-2-spiro-3′-8′-[[[(dimethylamino)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ266). To a solution of OZ209 (389 mg, 1.0 mmol) and triethylamine(202 mg, 2.0 mmol) in CH₂Cl₂ (10 ml) at 0° C. was addeddimethylcarbamoyl chloride (120 mg, 1.1 mmol). The mixture was stirredat rt for 16 h before being washed with water and brine, dried overMgSO₄, and concentrated. The crude product was crystallized from 50% aq.ethanol to afford trioxolane OZ266 (270 mg, 74%) as a colorless solid.mp 153-155° C. (50% aq. ethanol); ¹H NMR (500 MHz, CDCl₃) δ 1.14-1.33(m, 2H), 1.44-2.17 (m, 21H), 2.91 (s, 6H), 3.09 (app t, J=6.2 Hz, 2H),4.46 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.49, 26.88, 27.77,33.84, 34.79, 36.19, 36.39, 36.61, 36.80, 46.25, 108.85, 111.30, 158.43.Anal. Calcd for C₂₀H₃₂N₂O₄: C, 65.91; H, 8.85; N, 7.69. Found: C, 66.16;H, 8.80; N, 7.90.

[0271]cis-Adamantane-2-spiro-3′-8′-[[[(4′-methyl-1′-piperazinyl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ267). To a solution of OZ209 (389 mg, 1.0 mmol)-and triethylamine(404 mg, 4.0 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added4-methyl-1-piperazinecarbonyl chloride hydrochloride (240 mg, 1.2 mmol).The mixture was stirred at rt for 16 h before being washed with waterand brine, dried over MgSO₄, and concentrated. The crude product wascrystallized from 60% aq. ethanol to afford trioxolane OZ267 (280 mg,67%) as a colorless solid. mp 82° C. dec (60% aq. ethanol); ¹H NMR (500MHz, CDCl₃) δ 1.11-1.30 (m, 2H), 1.43-2.15 (m, 21H), 2.31 (s, 3H), 2.39(t, J=5.1 Hz, 4H), 3.09 (app t, J=6.2 Hz, 2H), 3.38 (t, J=5.1 Hz, 4H),4.59 (app t, J=5.5 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.45, 26.84,27.77, 33.78, 34.76, 36.35, 36.48, 36.76, 43.71, 46.08, 46.18, 54.64,108.77, 111.29, 157.69. Anal. Calcd for C₂₃H₃₇N₃O₄: C, 65.84; H, 8.89;N, 10.02. Found: C, 65.91; H, 8.64; N, 10.07.

[0272]N-(cis-Adamantane-2-spiro-3′-1′,2′,4′-trioxaspiro[4.5]decane-8′-methyl)oxamide(OZ268). To a solution of oxamic acid (107 mg, 1.2 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (290 mg, 1.5mmol), and 1-hydroxybenzotriazole (200 mg, 1.5 mmol) in DMF (15 ml)under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at rt for 16 h before being quenched with water (80 ml). Theprecipitate was collected by filtration to afford trioxolane OZ268 (320mg, 88%) as a colorless solid. mp 152-155° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 0.95-1.23 (m, 2H), 1.39-2.13 (m, 21H), 2.97 (app t, J=6.5 Hz, 2H),7.74 (s, 1H), 7.80 (s, 1H), 8.67 (app t, J=6.2 Hz, 1H); ¹³C NMR (125.7MHz, DMSO-d₆) δ 25.97, 26.38, 27.55, 33.30, 34.41, 35.47, 35.91, 36.25,44.03, 108.70, 110.62, 160.50, 162.38. Anal. Calcd for C₁₉H₂₈N₂O₅: C,62.62; H, 7.74; N, 7.69. Found: C, 62.80; H, 7.55; N, 7.89.

[0273]trans-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ269). A mixture of OZ167 (2.54 g, 6.0 mmol) and hydrazinemonohydrate (1.80 g, 36.0 mmol) in chloroform/ethanol (7:3, 60 ml) washeated at 55-65° C. for 24 h. After being cooled to rt, the solidbyproduct was filtered off and the filtrate was washed with water (2×40ml) and brine (20 ml). The combined aqueous layers were extracted withCH₂Cl₂ (3×30 ml). The CH₂Cl₂ extracts were washed with water (50 ml) andbrine (50 ml). The combined organic solutions were dried over MgSO₄ andconcentrated. The residue was dissolved in CH₂Cl₂ (10 ml) and treatedwith a solution of methanesulfonic acid (0.6 g) in CH₂Cl₂ (2 ml). Theproduct was precipitated by addition of ether (40 ml) and collected byfiltration to afford trioxolane OZ269 (1.80 g, 77%) as a colorlesssolid. mp 140-141° C.; ¹H NMR (500 MHz, CDCl₃).1.32-1.52 (m, 2H),1.54-2.15 (m, 21H), 2.76 (s, 3H), 2.87 (app t, J=6.3 Hz, 2H), 7.60 (s,3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44, 26.86, 27.24, 33.23, 34.56,34.71, 34.90, 36.33, 36.74, 39.29, 44.63, 108.06, 111.81. Anal. Calcdfor C₁₈H₃₁NO₆S.0.4H₂O: C, 53.84; H, 8.12; N, 3.49. Found: C, 53.51; H,7.64; N, 3.66.

[0274]cis-Adamantane-2-spiro-3′-8′-[[(aminoacetyl)amino]methyl]-1′,2′,4′-3 0trioxaspiro[4.5]decane mesylate (OZ271). To a solution ofN-phthaloylglycine (226 mg, 1.1 mmol), EDCI (290 mg, 1.5 mmol), and HOBt(200 mg, 1.5 mmol) in DMF (30 ml) under N₂ was added a solution of OZ209(cis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decanemesylate) (389 mg, 1.0 mmol) and triethylamine (101 mg, 1.0 mmol) in DMF(5 ml). The resulting mixture was stirred at rt for 16 h before beingquenched with water (80 ml). The precipitate was collected by filtrationto affordcis-adamantane-2-spiro-3′-8′-[[(2-phthalimidoacetyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(426 mg, 89%) as a colorless solid. mp 139-142° C.; ¹H NMR (500 MHz,CDCl₃).1.15-1.30 (m, 2H), 1.50-2.00 (m, 21H), 3.14 (t, J=6.6 Hz, 2H),4.33 (s, 2H), 7.72-7.77 (m, 2H), 7.85-7.90 (m, 2H). Step 2. A mixture ofcis-adamantane-2-spiro-3′-8′-[[(2-phthalimidoacetyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(420 mg, 0.88 mmol) and hydrazine monohydrate (300 mg, 5.36 mmol) inchloroform/ethanol (7:3, 10 ml) was heated at 55-60° C. for 24 h. Afterthe mixture was cooled to rt, the solid byproduct was filtered off. Thefiltrate was washed with water (2×10 ml) and brine (10 ml), dried overMgSO₄, and concentrated. The residue was dissolved in CH₂Cl₂/ether (1:4,10 ml) and treated with methanesulfonic acid (77 mg, 0.8 mmol). Theprecipitate was collected by filtration to afford trioxolane OZ271 (260mg, 66%) as a colorless solid. mp 153° C. dec; ¹H NMR (500 MHz, DMSO-d₆)δ 1.01-1.19 (m, 2H), 1.38-2.11 (m, 21H), 2.32 (s, 3H), 3.00 (app t,J=5.8 Hz, 2H), 3.54 (d, J=4.9 Hz, 2H), 7.94 (s, 3H), 8.31 (t, J=5.2 Hz,1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.96, 26.37, 27.52, 33.35, 34.42,35.71, 35.91, 36.24, 40.28, 43.96, 108.65, 110.68, 165.95. Anal. Calcdfor C₂₀H₃₄N₂O₇S: C, 53.79; H, 7.67; N, 6.27. Found: C, 53.60; H, 7.46;N, 6.10.

[0275]cis-Adamantane-2-spiro-3′-8′-[[(4′-morpholinylcarbonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ272). To a solution of OZ209(cis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decanemesylate) (389 mg, 1.0 mmol) and triethylamine (404 mg, 4.0 mmol) inCH₂Cl₂ (10 ml) at 0° C. was added 4-morpholinecarbonyl chloride (225 mg,1.5 mmol). The mixture was stirred at rt for 16 h, washed with water andbrine, dried over MgSO₄, and concentrated. The crude product wascrystallized from hexanes/ether (4:1) to afford trioxolane OZ272 (290mg, 71%) as a colorless solid. mp 141-142° C. (hexanes/ether, 4:1); ¹HNMR (500 MHz, CDCl₃) δ 1.06-1.35 (m, 2H), 1.42-2.18 (m, 21H), 3.11 (appt, J=5.9 Hz, 2H), 3.33 (t, J=4.8 Hz, 4H), 3.69 (t, J=4.9 Hz, 4H), 4.54(s, 1H); ¹³C NMR (125.7 MHz, CDCl₃).26.48, 26.87, 27.78, 33.80, 34.79,36.38, 36.51, 36.79, 44.02, 46.17, 66.46, 108.75, 111.36, 157.83. Anal.Calcd for C₂₂H₃₄N₂O₅: C, 65.00; H, 8.43; N, 6.89. Found: C, 64.84; H,8.42; N, 6.91.

[0276]cis-Adamantane-2-spiro-3′-8′-[[(3′-pyridinylcarbonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ273). To a solution ofcis-adamantane-2-spiro-3′-8′-aminomethyl-1′,2′,4′-trioxaspiro[4.5]decane(360 mg, 1.2 mmol) and triethylamine (370 mg, 3.6 mmol) in CH₂Cl₂ (12ml) at 0° C. was added nicotinoyl chloride (278 mg, 1.56 mmol). Themixture was stirred at rt for 16 h, washed with water and brine, driedover MgSO₄, and concentrated. The crude product was purified by flashchromatography (silica gel, 2% MeOH in CH₂Cl₂) to afford trioxolaneOZ273 (240 mg, 60%) as a colorless solid. mp 70-72° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.18-1.42 (m, 2H), 1.49-2.21 (m, 21H), 3.35 (app t, J=6.3 Hz,2H), 6.39 (s, 1H), 7.37-7.48 (m, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.73 (s,1H), 8.96 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.45, 26.85, 27.84,33.72, 34.77, 36.26, 36.37, 36.76, 45.38, 108.51, 111.44, 123.52,130.35, 135.09, 147.71, 152.20, 165.68. Anal. Calcd for C₂₃H₃₀N₂O₄: C,69.32; H, 7.59; N, 7.03. Found: C, 69.29; H, 7.56; N, 7.01.

[0277]Adamantane-2-spiro-3′-8′-fluoro-8′-phenyl-1′,2′,4′-trioxaspiro[4.5]decane(OZ274). To a stirred solution of phenyl carbinol (178 mg, 0.5 mmol),obtained by addition of phenyllithium to OZ05(Adamantane-2-spiro-3′-8′-oxo-1′,2′,4′-trioxaspiro[4.5]decane), in dryCH₂Cl₂ (5 ml) under N₂ at −78° C. was added DAST (88 mg, 0.55 mmol). Thereaction mixture was stirred at −78° C. for 1.5 h and poured into icewater (5 ml). The organic layer was separated, and the aqueous layer wasthen extracted with CH₂Cl₂ (3×5 ml). The combined organic extracts werewashed with water (10 ml), dried over MgSO₄, and concentrated. Thepurification of the crude product by flash chromatography (silica gel,1% ether in hexanes) followed by recrystallization from 5% ether inhexanes afforded trioxolane OZ274 (97 mg, 54%) as a colorless solid. mp94-96° C.; ¹H NMR (500 MHz, CDCl₃) δ 51.58-2.43 (m, 22H), 7.21-7.58 (m,5H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.47, 26.92, 30.14 (d, J=2.3 Hz),34.74, 34.95 (d, J=23.4 Hz), 35.03, 36.39, 36.77, 95.09 (d, J=174.9 Hz),107.82, 111.82, 123.92 (d, 9.6 Hz), 127.55 (d, J=1.4 Hz), 128.31 (d,J=1.4 Hz), 144.29 (d, J=21.5 Hz). Anal. Calcd for C₂₂H₂₇FO₃: C, 73.72;H, 7.59. Found: C, 73.90; H, 7.47.Adamantane-2-spiro-3′-8′-hydroxy-8′-(2′-pyridinylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ275). To a stirred solution of 2-picoline (279 mg, 3.0 mmol) in dryTHF (10 ml) under N₂ at −78° C. was added n-BuLi (1.6 M in hexanes, 1.9ml, 3.0 mmol). The resulting bright yellow solution was stirred at thesame temperature for 1 h before a solution of OZ05 (690 mg, 2.5 mmol) indry THF (15 ml) was added slowly. The mixture was allowed to reach 0°C., and then poured into ice water (50 ml), and extracted with ether(3×50 ml). The combined organic extracts were washed with brine (50 ml),dried over MgSO₄, and concentrated. The purification of the crudeproduct by flash chromatography (silica gel, 70% EtOAc in hexanes)followed by recrystallization from ethanol afforded trioxolane OZ275(385 mg, 41%) as a colorless solid. mp 128-130° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.41-2.25 (m, 22H), 2.88 (s, 2H), 5.82 (s, 1H), 7.11 (d, J=7.7Hz, 1H), 7.17 (dd, J=7.3, 4.6 Hz, 1H), 7.63 (ddd, J=7.7, 7.7, 1.9 Hz,1H), 8.49 (d, J=4.1 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.51, 26.89,29.93, 34.80, 35.03, 36.43, 36.83, 47.30, 70.09, 109.01, 111.30, 121.53,124.42, 136.89, 148.40, 159.55. Anal. Calcd for C₂₂H₂₉NO₄: C, 71.13; H,7.87; N, 3.77. Found: C, 71.31; H, 7.94; N, 3.93.

[0278]Adamantane-2-spiro-3′-8′-hydroxy-8′-(2′-benzothiazolylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ276). To a stirred solution of 2-methylbenzothiazole (244 mg, 1.6mmol) in dry THF (4 ml) under N₂ at −78° C. was added n-BuLi (1.6 M inhexanes, 1.1 ml, 1.8 mmol). The resulting bright yellow solution wasstirred at the same temperature for 1 h before a solution of OZ05 (500mg, 1.8 mmol) in dry THF (10 ml) was added slowly. The mixture wasallowed to reach 0° C., and then poured into ice water (15 ml), andextracted with ether (3×25 ml). The combined organic extracts werewashed with brine (25 ml), dried over MgSO₄, and concentrated. Thepurification of the crude product by flash chromatography (silica gel,30% EtOAc in hexanes) followed by recrystallization (ether/hexane 1:1)afforded trioxolane OZ276 (353 mg, 52%) as a colorless solid. mp130-132° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.58-2.29 (m, 22H), 3.19 (s, 2H),4.28 (br s, 1H), 7.31-7.43 (m, 1H), 7.44-7.53 (m, 1H), 7.86 (d, J=7.7Hz, 1H), 7.99 (d, J=8.2 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.49,26.88, 29.87, 34.71, 34.79, 34.80, 36.41, 36.80, 44.92, 70.19, 108.63,111.47, 121.44, 122.70, 125.06, 126.17, 134.35, 152.98, 168.22. Anal.Calcd for C₂₄H₂₉NO₄S: C, 67.42; H, 6.84; N, 3.28. Found: C, 67.70; H,6.76; N, 3.23.

[0279] cis-Adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-3 0methylpropyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ277). Step 1. A solution of OZ78(cis-Adamantane-2-spiro-3′-8′-carboxymethyl-1′,2′,4′-trioxaspiro[4.5]decane)(12.92 g, 40 mmol), HOBt (6.49 g, 48 mmol), and EDCI (9.20 g, 48 mmol)in DMF (300 ml) under N₂ was stirred at rt for 24 h. Under ice cooling,the reaction was quenched with water (150 ml). The precipitate wascollected by filtration, washed with 95% ethanol (150 ml), and dried toafford the OZ78 active ester (16.61 g, 95%) as a colorless solid. mp154-156° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.37-1.51 (m, 2H), 1.63-2.17 (m,21H), 2.72 (d, J=7.1 Hz, 2H), 7.39 (d, J=78.5 Hz, 1H), 7.43 (dd, J=8.2,7.2 Hz, 1H), 7.56 (dd, J=8.0, 7.4 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H). Step2. To a solution of the OZ78 active ester (13.19 g, 30 mmol) in CHCl₃(300 ml) was added rapidly a solution of 1,2-diamino-2-methylpropane(5.29 g, 60 mmol) in CHCl₃ (50 ml). The resulting mixture was stirred atrt for 1 h before being quenched with water (500 ml). After separationof the organic layer, the aqueous layer was extracted with CHCl₃ (2×100ml). The combined extracts were washed with water (3×500 ml) and brine(300 ml), dried over MgSO₄, and filtered. To the filtrate was added asolution of p-toluenesulfonic acid monohydrate (5.71 g, 30 mmol) inethanol (30 ml). After evaporation of the solvents, the residue wastreated with ethanol (100 ml), filtered, and washed with hexanes (200ml) to afford trioxolane OZ277 (14.25 g, 84%) as a colorless solid. mp160-162° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 1.01-1.17 (m, 2H), 1.16 (s,6H), 1.58-1.99 (m, 21H), 2.05 (d, J=7.1 Hz, 2H), 2.28 (s, 3H), 3.19 (d,J=6.3 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.70 (s,3H), 8.02 (t, J=6.2 Hz, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 20.92,23.47, 25.96, 26.36, 29.68, 32.71, 33.56, 34.40, 35.91, 36.23, 41.97,46.02, 54.52, 108.52, 110.63, 125.64, 128.20, 137.80, 145.82, 172.49.Anal. Calcd for C₂₉H₄₄N₂O₇S: C, 61.68; H, 7.85; N, 4.96. Found: C,61.46; H, 7.67; N, 4.76.

[0280]cis-Adamantane-2-spiro-3′-8′-[[(1′H-tetrazol-5′-ylarmino)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ278). To a solution of OZ78 (322 mg, 1.0 mmol), 5-aminotetrazole (103mg, 1.0 mmol), and 4-methylmorpholine (304 mg, 3 mmol) in DMF (10 ml) at0° C. was added benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (531 mg, 1.2 mmol). The resulting mixture wasstirred at rt for 3 days and filtered. After the filtrate wasconcentrated, the residue was crystallized from 40% aq. ethanol followedby recrystallization from CH₂Cl₂ to afford trioxolane OZ278 (68 mg, 17%)as a colorless solid. mp 150-152° C.; ¹H NMR (500 MHz, DMSO-d₆) δ1.01-1.23 (m, 2H), 1.41-2.07 (m, 21H), 2.35 (d, J=6.9 Hz, 2H), 11.94 (s,1H), 15.82 (s, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.95, 26.36, 29.53,32.80, 33.50, 34.40, 35.90, 36.23, 41.51, 108.40, 110.68, 149.95,171.13. Anal. Calcd for C₁₉H₂₇N₅O₄: C, 58.60; H, 6.99; N, 17.98. Found:C, 58.76; H, 7.05; N, 18.14.

[0281]cis-Adamantane-2-spiro-3′-8′-[(1′-piperazinylcarbonyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ279). To a solution of the OZ78 active ester (13.19 g, 30mmol) in CHCl₃ (300 ml) was added rapidly a solution of piperazine(12.92 g, 150 mmol) in CHCl₃ (50 ml). The resulting mixture was stirredat rt for 1.5 h before being quenched with water (500 ml). Afterseparation of the organic layer, the aqueous layer was extracted withCHCl₃ (2×100 ml). The. combined extracts were washed with water (3×500ml) and brine (300 ml), dried over MgSO₄, and filtered. To the filtratewas added a solution of p-toluenesulfonic acid monohydrate (5.71 g, 30mmol) in ethanol (30 ml). After evaporation of the solvents, the residuewas dissolved in CHCl₃ (70 ml), and the product was precipitated byadding isopropanol (420 ml), filtered, and washed with isopropanol/CHCl₃(6:1, 210 ml) and hexanes (300 ml). The solid was redissolved in CHCl₃(60 ml), precipitated by adding hexanes (600 ml), filtered, and washedwith hexanes (200 ml) to afford trioxolane OZ279 (12.58 g, 75%) as acolorless solid. mp 148-150° C.; ¹-H NMR (500 MHz, CDCl₃) δ 1.03-1.29(m, 2H), 1.49-2.05 (m, 21H), 2.15 (d, J=6.3 Hz, 2H), 2.39 (s, 3H), 3.18(s, 2H), 3.25 (s, 2H), 3.71 (s, 2H), 3.83 (s, 2H), 7.22 (d, J=7.7 Hz,2H), 7.71 (d, J=7.4 Hz, 2H), 9.25 (s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ21.35, 26.47, 26.85, 30.19, 33.00, 33.96, 34.77, 36.38, 36.78, 38.19,38.90, 42.36, 43.68, 43.78, 108.41, 111.37, 125.66, 129.22, 140.94,141.11, 170.45. Anal. Calcd for C₂₉H₄₂N₂O₇S: C, 61.90; H, 7.52; N, 4.98.Found: C, 62.18; H, 7.68; N, 4.95.

[0282]cis-Adamantane-2-spiro-3′-8′-[[(2′-hydroxybenzoyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ280). To a mixture of salicylic acid (166 mg, 1.2 mmol), EDCI (290mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF (10 ml) under N₂ wasadded a solution of OZ209(cis-Adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decanemesylate) (389 mg, 1.0 mmol) and triethylamine (101 mg, 1.0 mmol) in DMF(5 ml). The resulting mixture was stirred at rt for 16 h before beingquenched with water (70 ml). The precipitate was collected by filtrationand recrystallized from ethanol to afford trioxolane OZ280 (175 mg, 42%)as a colorless solid. mp 149-150° C. (ethanol); ¹H NMR (500 MHz, CDCl₃)δ 1.21-1.41 (m, 2H), 1.47-2.07 (m, 21H), 3.32 (app t, J=6.3 Hz, 2H),6.40 (s, 1H), 6.85 (ddd, J=7.4, 7.4, 1.1 Hz, 1H), 6.99 (dd, J=8.2, 0.8Hz, 1H), 7.35 (dd, J=8.0, 1.4 Hz, 1H), 7.40 (ddd, J=7.8, 7.8, 1.5 Hz,1H), 12.31 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 526.43, 26.82, 27.82,33.69, 34.76, 36.21, 36.34, 36.74, 44.86, 108.49, 111.47, 114.19,118.60, 118.68, 125.13, 134.23, 161.55, 170.01. Anal. Calcd forC₂₄H₃₁N_(O) ₅: C, 69.71; H, 7.56; N, 3.39. Found: C, 69.57; H, 7.66; N,3.48.

[0283]cis-Adamantane-2-spiro-3′-8′-[[(2′-amino-2′-methylpropionyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ281). To a mixture of 2-aminoisobutyric acid (618 mg, 6.0 mmol), EDCI(1.16 g, 6.0 mmol), and HOBt (800 mg, 6.0 mmol) in DMF (150 ml) under N₂was added a solution of OZ209 (1.47 g, 3.0 mmol) and triethylamine (404mg, 4.0 mmol) in DMF (15 ml). The resulting mixture was stirred at rtfor 48 h and concentrated. The residue was treated with saturated aq.NaHCO₃ (40 ml), diluted with water (40 ml), then basified with 1M aq.NaOH to pH=8, and extracted with CHCl₃ (3×60 ml). The combined extractswere washed with water and brine, dried over MgSO₄, and concentrated.The crude product was crystallized from 50% aq. ethanol to affordtrioxolane OZ281 (0.92 g, 81%) as a colorless solid. mp 153-155° C.(ether/CH₂Cl₂, 1:1); ¹H NMR (500 MHz, CDCl₃) δ 1.19-1.35 (m, 2H), 1.36(s, 6H), 1.43-2.09 (m, 23H), 3.09 (app t, J=6.5 Hz, 2H), 7.73 (s, 1H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.48, 26.88, 27.75, 29.36, 33.82, 34.79,36.39, 36.80, 44.36, 54.92, 108.69, 111.32, 177.45. Anal. Calcd forC₂₁H₃₄N₂O₄: C, 66.64; H, 9.05; N, 7.40. Found: C, 66.48; H, 9.05; N,7.52.

[0284]cis-Adamantane-2-spiro-3′-8′-[[[(4′-hydroxy-3′-pyridinyl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ282). To a mixture of 6-hydroxynicotinic acid (167 mg, 1.2 mmol),EDCI (290 mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF (10 ml)under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at rt for 16 h before being quenched with water (70 ml). Theprecipitate was collected by filtration to afford trioxolane OZ282 (390mg, 94%) as a colorless solid. mp 150-152° C.; ¹H NMR (500 MHz, CDCl₃) δ1.17-1.39 (m, 2H), 1.47-2.09 (m, 21H), 3.26 (app t, J=6.2 Hz, 2H), 6.54(d, J=9.3 Hz, 1H), 6.62 (t, J=5.7 Hz, 1H), 7.83 (dd, J=9.5, 2.3 Hz, 1H),8.06 (d, 1.9 Hz, 1H), 12.62 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.44, 26.83, 27.85, 33.71, 34.77, 36.24, 36.35, 36.75, 45.28, 108.57,111.44, 114.94, 119.53, 136.62, 139.61, 164.25, 164.76. Anal. Calcd forC₂₃H₃₀N₂O₅.0.67H₂O: C, 64.77; H, 7.40; N, 6.57. Found: C, 64.30; H,7.18; N, 6.78.

[0285]cis-Adamantane-2-spiro-3′-8′-[[[(3′-amino-1′H-triazol-5′-yl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ283). To a mixture of 3-amino-1H-1,2,4-triazole-5-carboxylic acidhemihydrate (164 mg, 1.2 mmol), EDCI (290 mg, 1.5 mmol), and HOBt (200mg, 1.5 mmol) in DMF (10 ml) under N₂ was added a solution of OZ209 (389mg, 1.0 mmol) and triethylamine (101 mg, 1.0 mmol) in DMF (5 ml). Theresulting mixture was stirred at rt for 48 h before being quenched withwater (70 ml). The precipitate was collected by filtration to affordtrioxolane OZ283 (325 mg, 81%) as a colorless solid. mp 146° C. dec; ¹HNMR (500 MHz, DMSO-d₆) δ 1.01-1.19 (m, 2H), 1.41-2.05 (m, 21H), 3.04(app t, J=6.6 Hz, 2H), 6.05 (br s, 2H), 7.98 (br s, 1H), 12.37 (br s,1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.98, 26.39, 27.59, 33.37, 34.42,35.76, 35.92, 36.26, 43.58, 108.79, 110.62, 155.04 (br s), 157.07 (brs), 159.77 (br s). Anal. Calcd for C₂₀H₂₉N₅O₄: C, 59.54; H, 7.24; N,17.36. Found: C, 59.38; H, 7.33; N, 17.57.

[0286]cis-Adamantane-2-spiro-3′-8′-[[[(2′-amino-3′-pyridinyl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ284). To a mixture of 2-aminonicotinic acid (168 mg, 1.2mmol), EDCI (290 mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF (10ml) under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at rt for 16 h before being quenched with water (70 ml). Theprecipitate was collected by filtration, re-dissolved in CH₂Cl₂ (3 ml),and treated with a solution of methanesulfonic acid (96 mg, 1.0 mmol) inCH₂Cl₂ (21 ml). The solid was collected by filtration to affordtrioxolane OZ284 (280 mg, 55%) as a colorless solid. mp 164-165° C.(CH₂Cl₂); ¹H NMR (500 MHz, DMSO-d₆) δ 1.03-1.23 (m, 2H) 1.46-1.98 (m,21H), 2.40 (s, 3H), 3.13 (app t, J=6.1 Hz, 2H), 6.99 (dd, J=7.8, 6.4 Hz,1H), 8.15 (dd, J=6.3, 1.4 Hz, 1H), 8.42 (dd, J=7.8, 1.5 Hz, 1H), 8.46(br s, 2H), 8.94 (t, J=5.9 Hz, 1H), 13.48 (br s, 1H); ¹³C NMR (125.7MHz, DMSO-d₆) δ 25.98, 26.39, 27.74, 33.40, 34.42, 35.59, 35.92, 36.25,44.48, 108.70, 110.68, 111.70, 115.29, 140.11, 143.26, 153.34, 164.69.Anal. Calcd for C₂₄H₃₅N₃O₇S: C, 56.56; H, 6.92; N, 8.25. Found: C,56.35; H, 6.96; N, 8.40.

[0287]cis-Adamantane-2-spiro-3′-8′-[(3′-oxo-1′-piperazinyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ285). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), piperazine-2-one (114 mg, 1.0 mmol), and acetic acid (60mg, 1.0 mmol) in 1,2-dichloroethane (15 ml) under N₂ was stirred at rtfor 10 min before sodium triacetoxyborohydride (322 mg, 1.5 mmol) wasadded. The resulting mixture was stirred at rt for 4 h and then quenchedwith saturated aq. NaHCO₃ (15 ml). The organic layer was separated, andthe aqueous layer was extracted with CH₂Cl₂ (2×15 ml). The combinedorganic extracts were washed with water and brine, dried over MgSO₄, andconcentrated. The crude product was crystallized from hexanes/CH₂Cl₂(4:1) to afford trioxolane OZ285 (210 mg, 56%) as a colorless solid. mp157° C. dec; ¹H NMR (500 MHz, CDCl₃) δ 1.07-1.25 (m, 2H), 1.41-2.05 (m,21H), 2.17-2.27 (m, 2H), 2.61 (br s, 2H), 3.03-3.15 (m, 2H), 3.35 (br s,2H), 6.55 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.45, 26.85, 28.35,33.57, 33.91, 34.76, 34.77, 36.35, 36.77, 41.33, 49.67, 57.21, 63.41,108.91, 111.28, 169.75. Anal. Calcd for C₂₁H₃₂N₂O₄: C, 66.99; H, 8.57;N, 7.44. Found: C, 66.78; H, 8.51; N, 7.46.

[0288]cis-Adamantane-2-spiro-3′-8′-[[[4′-(aminocarbonyl)phenyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ286). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), 4-aminobenzamide (136 mg, 1.0 mmol), and acetic acid (60mg, 1.0 mmol) in 1,2-dichloroethane (15 ml) under N₂ was stirred at rtfor 10 min before sodium triacetoxyborohydride (322 mg, 1.5 mmol) wasadded. The resulting mixture was stirred at rt for 4 h and then quenchedwith saturated aq. NaHCO₃ (20 ml). The organic layer was separated, andthe aqueous layer was extracted with CH₂Cl₂ (2×15 ml). The combinedorganic extracts were washed with water and brine, dried over MgSO₄, andconcentrated. The crude product was crystallized from 95% aq. ethanol toafford trioxolane OZ286 (120 mg, 29%) as a colorless solid. mp 153-156°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 1.03-1.25 (m, 2H) 1.46-2.08 (m, 21H),2.91 (br s, 2H), 6.21 (s, 1H), 6.52 (d, J=8.2 Hz, 2H), 6.80 (br s, 1H),7.50 (br s, 1H), 7.61 (d, J=8.2 Hz, 2H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ26.00, 26.40, 27.96, 33.54, 34.45, 35.25, 35.94, 36.28, 48.05, 108.89,110.67, 120.70, 129.26, 151.68, 168.17. Anal. Calcd forC₂₄H₃₂N₂O₄.1.5H₂O: C, 65.58; H, 8.03; N, 6.37. Found: C, 65.86; H, 7.82;N, 6.77.

[0289]cis-Adamantane-2-spiro-3′-8′-[[(2′-amino-2′-methylpropyl)amino]methyl]-30 1′,2′,4′-trioxaspiro[4.5]decane dimesylate (OZ287). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), 1,2-diamino-2-methylpropane (88 mg, 1.0 mmol), and aceticacid (60 mg, 1.0 mmol) in 1,2-dichloroethane (10 ml) under N₂ wasstirred at rt for 10 min before sodium triacetoxyborohydride (322 mg,1.5 mmol) was added. The resulting mixture was stirred at rt for 4.5 hand then quenched with saturated aq. NaHCO₃ (20 ml). The organic layerwas separated and the aqueous layer was extracted with CH₂Cl₂ (2×15 ml).The combined organic extracts were washed with water and brine, driedover MgSO₄, and concentrated. The crude product was re-dissolved inCH₂Cl₂ (3 ml), treated with a solution of methanesulfonic acid (192 mg,2.0 mmol) in CH₂Cl₂ (2 ml), and diluted with ether (20 ml). The solidwas obtained by filtration to afford trioxolane OZ287 (236 mg, 42%) as acolorless solid. mp 158° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 1.08-1.25(m, 2H), 1.36 (s, 6H), 1.58-1.99 (m, 21H), 2.40 (s, 6H), 2.89 (br s,2H), 3.16 (br s, 2H), 8.14 (s, 3H), 8.28 (s, 2H); ¹³C NMR (125.7 MHz,DMSO-d₆) δ 23.76, 25.97, 26.38, 27.42, 32.53, 33.06, 34.42, 34.43,35.91, 36.24, 52.24, 53.79, 54.60, 108.22, 110.85. Anal. Calcd forC₂₃H₄₄N₂O₉S₂.0.2CH₂Cl₂: C, 48.57; H, 7.80; N, 4.88. Found: C, 48.36; H,7.43; N, 4.91.

[0290]cis-Adamantane-2-spiro-3′-8′-(4′-hydroxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ288). Step 1. To a mixture of 4-(4-hydroxyphenyl)cyclohexanone (19.0g, 0.1 mol) and triethylamine (40.4 g, 0.4 mol) in CH₂Cl₂ (700 ml) at 0°C. was added dropwise acetyl chloride (15.7 g, 0.2 mol). After theaddition was finished, the reaction mixture was warmed to rt and stirredovernight. The reaction mixture was washed with water and brine, driedover MgSO₄, and concentrated. The crude product was crystallized from95% aq. ethanol to afford 4-(4-acetoxyphenyl)-cyclohexanone (17.6 g,76%) as a colorless solid. mp 104-106° C. (95% aq. ethanol); ¹H NMR (500MHz, CDCl₃) δ 1.88-1.98 (m, 2H), 2.20-2.26 (m, 2H), 2.48-2.54 (m, 4H),2.30 (s, 3H), 3.00-3.07 (m, 1H), 7.03 (d, J=8.7 Hz, 2H), 7.25 (d, J=8.7Hz, 2H). Step 2. A solution of O-methyl 2-adamantanone oxime (16.0 g, 89mmol) and 4-(4-acetoxyphenyl)cyclohexanone (13.8 g, 59 mmol) incyclohexane (400 ml) and CH₂Cl₂ (100 ml) was treated with ozoneaccording to the general procedure. The crude product was trituratedwith ethanol (200 ml) to affordadamantane-2-spiro-3′-8′-(4′-acetoxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane(16.4 g, 70%) as a colorless solid. mp 149-151° C. (ethanol); ¹H NMR(500 MHz, CDCl₃) δ 1.64-2.08 (m, 22H), 2.29 (s, 3H), 2.50-2.60 (m, 1H),7.00 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H). Step 3. A mixture ofadamantane-2-spiro-3′-8′-(4′-acetoxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane(16.4 g, 41 mmol) and 15% aq. KOH (65 ml) in THF/MeOH (1:2, 500 ml) washeated at 50° C. for 4 h. After being cooled to rt, the reaction mixturewas concentrated to 70 ml, diluted with water (70 ml), and acidifiedwith acetic acid (30 ml). The precipitate was collected by filtration toafford trioxolane OZ288 (14.36 g, 98%) as a colorless solid. mp 136-138°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.56-2.18 (m, 22H), 2.41-2.58 (m, 1H),5.90 (br s, 1H), 6.76 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.5 Hz, 2H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.49, 26.89, 31.65, 34.75, 34.80, 36.41, 36.81,42.05, 108.46, 111.35, 115.22, 127.71, 138.03, 154.26. Anal. Calcd forC₂₂H₂₈O₄: C, 74.13; H, 7.92. Found: C, 73.90; H, 7.85.

[0291]cis-Adamantane-2-spiro-3′-8′-[[(ethoxycarbonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ289). To a solution of OZ209 (272 mg, 0.7 mmol) and triethylamine(271 mg, 2.7 mmol) in CH₂Cl₂ (15 ml) at 0° C. was added a solution ofethyl chloroformate (109 mg, 1 mmol) in CH₂Cl₂ (2 ml). After beingstirred at rt for 5 h, the reaction mixture was washed with water andbrine, dried over MgSO₄, and concentrated. The crude product wascrystallized from hexanes/ether (9:1) to afford trioxolane OZ289 (160mg, 63%) as a colorless solid. mp 69-71° C.; ¹H NMR (500 MHz, CDCl₃) δ1.12-1.39 (m, 5H), 1.42-2.09 (m, 21H), 3.04 (app t, J=6.3 Hz, 2H), 4.10(q, J=7.4 Hz, 2H), 4.69 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 14.62,26.47, 26.87, 27.60, 33.76, 34.79, 36.38, 36.61, 36.79, 46.22, 60.73,108.68, 111.35, 156.70. Anal. Calcd for C₂₀H₃₁NO₅: C, 65.73; H, 8.55; N,3.83. Found: C, 66.00; H, 8.69; N, 4.00.

[0292]cis-Adamantane-2-spiro-3′-8′-[[(2′-ethoxy-2′-oxoethyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ290). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (584mg, 2.0 mmol), glycine ethyl ester hydrochloride (280 mg, 2.0 mmol), andtriethylamine (202 mg, 2.0 mmol) in 1,2-dichloroethane (16 ml) under N₂was stirred at rt for 10 min before sodium triacetoxyborohydride (644mg, 3.0 mmol) was added. The resulting mixture was stirred at rt for 5h, quenched with saturated aq. NaHCO₃ (20 ml), and basified with 1 M aq.NaOH to pH=8. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (2×15 ml). The combined organic extracts werewashed with water and brine, dried over MgSO₄, and concentrated. Thecrude product was re-dissolved in CH₂Cl₂/ether (1:3, 10 ml) and treatedwith a solution of methanesulfonic acid (198 mg, 2.0 mmol) in ether (2ml). The precipitate was obtained by filtration to afford trioxolaneOZ290 (346 mg, 36%) as a colorless solid. mp 109-112° C.; ¹H NMR (500MHz, DMSO-d₆) δ 1.03-1.21 (m, 2H), 1.23 (t, J=7.0 Hz, 3H), 1.57-1.99 (m,21H), 2.34 (s, 3H), 2.84 (br s, 2H), 3.97 (s, 2H), 4.21 (q, J=7.1 Hz,2H), 8.97 (s, 2H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 14.11, 25.98, 26.39,27.36, 32.56, 32.97, 34.42, 34.43, 35.92, 36.25, 47.35, 51.94, 61.90,108.21, 110.83, 166.76. Anal. Calcd for C₂₂H₃₇NO₈S: C, 55.56; H, 7.84;N, 2.95. Found: C, 55.73; H, 7.71; N, 2.96.

[0293]cis-Adamantane-2-spiro-3′-8′-[[[(ethylamino)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ291). To a solution of OZ209 (272 mg, 0.7 mmol) and triethylamine (71mg, 0.7 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added a solution of ethylisocyanate (60 mg, 0.84 mmol). After being stirred at rt for 2 h, thereaction mixture was washed with water and brine, dried over MgSO₄, andconcentrated. The crude product was crystallized from 35% aq. ethanol toafford trioxolane OZ291 (155 mg, 61%) as a colorless solid. mp 112-116°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.13 (t, J=7.3 Hz, 3H), 1.15-1.29 (m, 2H),1.42-2.09 (m, 21H), 3.04 (d, J=5.4 Hz, 2H), 3.20 (q, J=7.3 Hz, 2H), 4.39(br s, 1H), 4.52 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃), 15.45, 26.46,26.85, 27.74, 33.79, 34.77, 35.37, 36.37, 36.78, 45.81, 108.74, 111.33,158.19. Anal. Calcd for C₂₀H₃₂N₂O₄: C, 65.91; H, 8.85; N, 7.69. Found:C, 65.73; H, 8.65; N, 7.53.

[0294]cis-Adamantane-2-spiro-3′-8′-[[(2′-pyridinylmethyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanedimesylate (OZ292). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), 2-(aminomethyl)pyridine (108 mg, 1.0 mmol), and aceticacid (60 mg, 1 mmol) in 1,2-dichloroethane (10 ml) under N₂ was stirredat rt for 10 min before sodium triacetoxyborohydride (322 mg, 1.5 mmol)was added. The resulting mixture was stirred at rt for 4 h and thenquenched with saturated aq. NaHCO₃ (20 ml). The organic layer wasseparated, and the aqueous layer was extracted with CHCl₃ (2×15 ml). Thecombined organic extracts were washed with water and brine, dried overMgSO₄, and concentrated. The crude product was purified by flashchromatography (silica gel, 2-10% MeOH in CH₂Cl₂) to give the desiredamine (250 mg). The free amine was dissolved in ether (5 ml) and treatedwith a solution of methanesulfonic acid (130 mg) in ether (5 ml). Theprecipitate was triturated with CH₂Cl₂ to afford trioxolane OZ292 (145mg, 25%) as a colorless solid. mp 142-145° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 1.05-1.25 (m, 2H), 1.54-1.99 (m, 21H), 2.40 (s, 6H), 2.88 (d, J=5.2Hz, 2H), 4.33 (s, 2H), 7.50 (dd, J=6.2, 6.2 Hz, 1H), 7.58 (d, J=8.0 Hz,1H), 7.97 (dd, J=7.3, 7.3 Hz, 1H), 8.35 (br s, 1H), 8.67 (d, J=4.6 Hz,1H), 8.99 (s, 2H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 25.97, 26.38, 27.40,32.73, 33.02, 34.42, 34.44, 35.92, 36.25, 50.51, 51.93, 108.24, 110.83,123.97, 124.16, 138.42, 148.58, 151.47. Anal. Calcd forC₂₅H₄₀N₂O₉S₂.0.33CH₂Cl₂: C, 50.29; H, 6.77; N, 4.63. Found: C, 49.86; H,6.66; N, 4.56.

[0295] cis-Adamantane-2-spiro-3′-8′-[(3′-pyridinylamino)methyl-1′,2′,4′-trioxaspiro[4.5]decane (OZ293). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), 3-aminopyridine (84 mg, 1.0 mmol), and acetic acid (60mg, 1 mmol) in 1,2-dichloroethane (10 ml) under N₂ was stirred at rt for10 min before sodium triacetoxyborohydride (322 mg, 1.5 mmol) was added.The resulting mixture was stirred at rt for 4 h, quenched with saturatedaq. NaHCO₃ (15 ml), and basified with 1 M aq. NaOH to pH=8. The organiclayer was separated, and the aqueous layer was extracted with CHCl₃(2×10 ml). The combined organic extracts were washed with water andbrine, dried over MgSO₄, and concentrated. The crude product wascrystallized from CH₂Cl₂/ether (1:5) to afford trioxolane OZ293 (100 mg,27%) as a colorless solid. mp 134-138° C.; ¹H NMR (500 MHz, CDCl₃) δ1.19-1.37 (m, 2H), 1.45-2.09 (m, 21H), 3.01 (d, J=6.6 Hz, 2H), 3.77 (brs, 1H), 6.85 (d, J=8.2 Hz, 1H), 7.08 (dd, J=8.0, 4.7 Hz, 1H), 7.94 (s,1H), 8.01 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.46, 26.86, 28.08,33.83, 34.78, 34.79, 35.97, 36.38, 36.77, 49.08, 108.66, 111.44, 118.34,123.74, 135.81, 138.41, 144.27. Anal. Calcd for C₂₂H₃₀N₂O₃: C, 71.32; H,8.16; N, 7.56. Found: C, 71.54; H, 7.87; N, 7.49.

[0296]cis-Adamantane-2-spiro-3′-8′-[[(4′-formyl-1′-piperazinyl)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ294). To a solution of the OZ78 active ester (440 mg, 1.0 mmol) inCHCl₃ (20 ml) was added a solution of 1-piperazinecarboxaldehyde (137mg, 1.2 mmol) in CHCl₃ (1 ml). The resulting mixture was stirred at rtfor 2 h before removal of the solvent. The residue was crystallized fromethanol/water (1:2) to afford trioxolane OZ294 (242 mg, 58%, 2:1 mixtureof rotamers) as a colorless solid. mp 142-144° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.15-1.32 (m, 2H), 1.45-2.09 (m, 21H), 2.20-2.28 (m, 2H),3.32-3.78 (m, 8H), 8.10 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.46,26.84, 30.27, 33.18, 34.01, 34.77, 36.38, 36.77, 39.26, 39.99, 40.22,41.02, 42.15, 45.15, 45.33, 45.70, 46.25, 108.49, 111.39, 160.74,160.92, 170.55, 170.72. Anal. Calcd for C₂₃H₃₄N₂O₅: C, 66.00; H, 8.19;N, 6.69. Found: C, 66.16; H, 7.95; N, 6.46.

[0297]cis-Adamantane-2-spiro-3′-8′-[[[(2′-pyridinylmethyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ295). To a solution of the OZ78 active ester (440 mg, 1.0mmol) in CHCl₃ (20 ml) was added a solution of 2-(aminomethyl)pyridine(130 mg, 1.2 mmol) in CHCl₃ (2 ml). The resulting mixture was stirred atrt for 2 h before being quenched with water (20 ml). After seperation ofthe organic layer, the aqueous layer was extracted with CHCl₃ (2×20 ml).The combined extracts were washed with water (2×30 ml) and brine (20ml), dried over MgSO₄, filtered, and concentrated. The residue wasdissolved in ether (10 ml) and CH₂Cl₂ (10 ml) and treated with asolution of methanesulfonic acid (96 mg, 1.0 mmol) in CH₂Cl₂ (1 ml).After evaporation of the solvents, the residue was crystallized fromether/ethanol (10:1) to afford trioxolane OZ295 (450 mg, 88%) as acolorless solid. mp 152-154° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.34 (m,2H), 1.55-2.09 (m, 21H), 2.19 (d, J=7.1 Hz, 2H), 2.91 (s, 3H), 4.74 (d,J=6.0 Hz, 2H), 7.81 (dd, J=6.7, 6.7 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H),8.37 (dd, J=7.8, 7.8 Hz, 1H), 8.55 (t, J=5.9 Hz, 1H), 8.67 (d, J=5.5 Hz,1H), 16.98 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 5 26.42, 26.81,29.85, 33.24, 33.93, 34.74, 36.30, 36.75, 39.36, 40.87, 42.10, 108.46,111.20, 125.19, 127.81, 141.32, 145.72, 154.52, 173.54. Anal. Calcd forC₂₅H₃₆N₂O₇S: C, 59.03; H, 7.13; N, 5.51. Found: C, 59.11; H, 7.15; N,5.36.

[0298]cis-Adamantane-2-spiro-3′-8′-[[(3′-oxo-1′-piperazinyl)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ296). To a solution of the OZ78 active ester (440 mg, 1.0 mmol) inCHCl₃ (20 ml) was added piperazin-2-one (120 mg, 1.2 mmol). Theresulting mixture was stirred at rt for 3 h before removal of thesolvent. The residue was crystallized from ethanol/water (1:1) to affordtrioxolane OZ296 (207 mg, 51%, 3:2 mixture of rotamers) as a colorlesssolid. mp 150-152° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.17-1.34 (m, 2H),1.57-2.09 (m, 21H), 2.21 (d, J=6.8 Hz, 1.2H), 2.24 (d, J=6.8 Hz, 0.8H),3.39 (s, 1.2H), 3.42 (s, 0.8H), 3.67 (t, J=5.0 Hz, 0.8H), 3.82 (t, J=5.4Hz, 1.2H), 4.12 (s, 1.2H), 4.25 (s, 0.8H), 6.42 (s, 0.6H), 6.58 (s,0.4H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.47, 26.85, 30.20, 30.26, 32.98,34.00, 34.78, 36.38, 36.78, 38.31, 39.34, 39.48, 40.83, 41.34, 42.40,46.06, 49.01, 108.46, 108.50, 111.35, 111.43, 166.60, 167.91, 170.37,170.62. Anal. Calcd for C₂₂H₃₂N₂O₅: C, 65.32; H, 7.97; N, 6.93. Found:C, 65.17; H, 7.78; N, 6.79.

[0299]cis-Adamantane-2-spiro-3′-8′-[[(4′-hydroxy-1′-piperidinyl)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ297). To a solution of the OZ78 active ester (440 mg, 1.0 mmol) inCHCl₃ (20 ml) was added 4-hydroxypiperidine (121 mg, 1.2 mmol). Theresulting mixture was stirred at rt for 1 h before being quenched withwater (20 ml). After separation of the organic layer, the aqueous layerwas extracted with CHCl₃ (2×20 ml). The combined extracts were washedwith water (3×30 ml) and brine (20 ml), dried over MgSO₄, filtered, andconcentrated. The residue was crystallized from ether/CHCl₃ (10:1) toafford trioxolane OZ297 (152 mg, 37%) as a colorless solid. mp 154-156°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.35 (m, 2H), 1.41-1.59 (m, 2H),1.60-2.09 (m, 23H), 2.23 (d, J=7.1 Hz, 2H), 3.09-3.31 (m, 2H), 3.68-3.82(m, 1H), 3.87-4.03 (m, 1H), 4.05-4.21 (m, 1H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.49, 26.86, 30.28, 33.39, 34.01, 34.07, 34.66, 34.78, 36.39,36.80, 38.92, 39.22, 42.97, 67.20, 108.64, 111.32, 170.39. Anal. Calcdfor C₂₃H₃₅NO₅: C, 68.12; H, 8.70; N, 3.45. Found: C, 68.19; H, 8.56; N,3.26.

[0300]cis-Adamantane-2-spiro-3′-8′-[[[4′-(aminosulfonyl)phenyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ298). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), sulfanilamide (172 mg, 1.0 mmol), and acetic acid (60 mg,1 mmol) in 1,2-dichloroethane (10 ml) under N₂ was stirred at rt for 10min before sodium triacetoxyborohydride (322 mg, 1.5 mmol) was added.The resulting mixture was stirred at rt for 4 h, quenched with saturatedaq. NaHCO₃ (15 ml), and concentrated to 16 ml. The precipitate wascollected by filtration and recrystallized from hexanes/ether (5:1) toafford trioxolane OZ298 (220 mg, 49%) as a colorless solid. mp 153-155°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.19-1.41 (m, 2H), 1.55-2.09 (m, 21H),3.05 (app t, J=6.2 Hz, 2H), 4.28 (s, 1H), 4.69 (s, 2H), 6.57 (d, J=8.5Hz, 2H), 7.69 (d, J=8.8 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.45,26.85, 28.04, 33.78, 34.77, 34.78, 35.91, 36.38, 36.76,48.84, 108.55,111.51, 111.56, 128.45, 128.61, 151.72. Anal. Calcd for C₂₃H₃₂N₂O₅S: C,61.58; H, 7.19; N, 6.24. Found: C, 61.61; H, 7.35; N, 6.30.

[0301]cis-Adamantane-2-spiro-3′-8′-[(2′-pyrimidinylsulfonyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ299). Step 1. To a mixture of OZ119(cis-Adamantane-2-spiro-3′-8′-hydroxymethyl-1′,2′,4′-trioxaspiro[4.5]decane)(588 mg, 2 mmol) and triphenylphosphine (628 mg, 2.4 mmol) in benzene(10 ml) at rt under N₂ was added dropwise a solution of DIPAD (486 mg,2.4 mmol) in benzene (2 ml). After 5 min, 2-pyrimidinethiol (224 mg, 2mmol) in benzene (5 ml) was added slowly over a period of 20 min. Thestirring was continued for 24 h before removal of the solvent. The crudeproduct was purified by flash chromatography (silica gel, 15% ethylacetate in hexanes) to givecis-adamantane-2-spiro-3′-8′-[(2′-pyrimidinylthio)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(420 mg, 54%) as a colorless solid. mp 140-142° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.21-1.42 (m, 2H), 1.60-2.11 (m, 21H), 3.09 (d, J=6.9 Hz, 2H),6.95 (t, J=4.8 Hz, 1H), 8.50 (d, J=4.7 Hz, 2H). Step 2. To a solution ofthe above thioether (396 mg, 1.0 mmol) in CH₂Cl₂ (5 ml) at 0° C. wasadded dropwise a solution of 3-chloroperoxybenzoic acid (70% reagent,790 mg, 3.2 mmol) in CHCl₃/CH₂Cl₂ (1:1, 16 ml). After 2 h, the mixturewas allowed to warm up to rt and stirred overnight before being quenchedwith saturated aq. NaHCO₃ (40 ml). The organic layer was separated, andthe aqueous layer was extracted with CHCl₃ (2×20 ml). The combinedorganic extracts were washed with water and brine, dried over MgSO₄, andconcentrated. The crude product was purified by flash chromatography(silica gel, 20% to 50% ethyl acetate in hexanes) to afford trioxolaneOZ299 (315 mg, 73%) as a colorless solid. mp 152-154° C.; ¹H NMR (500MHz, CDCl₃) δ 1.32-1.49 (m, 2H), 1.61-2.07 (m, 20H), 2.12-2.29 (m, 1H),3.47 (d, J=6.8 Hz, 2H), 7.57 (dd, J=4.9, 4.9 Hz, 1H), 8.96 (d, J=4.9 Hz,2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44, 26.82, 30.04, 30.87, 33.66,34.76, 36.35, 36.75, 56.34, 107.78, 111.59, 123.71, 158.66, 166.30.Anal. Calcd for C₂₁H₂₈N₂O₅S: C, 59.98; H, 6.71; N, 6.66. Found: C,60.16; H, 6.78; N, 6.77.

[0302]cis-Adamantane-2-spiro-3′-8′-[[(3′-carboxy-1′-oxopropyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ300). To a solution of OZ209 (389 mg, 1 mmol) and triethylamine (101mg, 1 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added succinic anhydride (100mg, 1 mmol). After being stirred at rt overnight, the reaction mixturewas washed with water and brine, dried over MgSO₄, and concentrated toafford trioxolane OZ300 (160 mg, 41%) as a colorless solid. mp 152-154°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 0.92-1.11 (m, 2H) 1.34-2.07 (m, 21H),2.29 (t, J=7.0 Hz, 2H), 2.39 (t, J=6.8 Hz, 2H), 2.88 (app t, J=6.2 Hz,2H), 7.82 (t, J=5.6 Hz, 1H), 12.02 (s, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆)δ 25.97, 26.38, 27.61, 29.37, 30.14, 33.41, 34.41, 35.85, 35.91, 36.25,43.86, 108.74, 110.59, 171.01, 173.98. Anal. Calcd for C₂₁H₃₁N_(O) ₆: C,64.10; H, 7.94; N, 3.56. Found: C, 63.85; H, 7.86; N, 3.54.

[0303]cis-Adamantane-2-spiro-3′-8′-[(4′-pyridinyloxy)methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ301). A mixture of diisopropyl azodicarboxylate (243 mg, 1.2mmol) and triphenylphosphine (315 mg, 1.2 mmol) in THF (5 ml) underargon was stirred at 0° C. for 30 min before OZ119 (294 mg, 1 mmol) and4-hydroxypyridine (114 mg, 1.2 mmol) were added. The resulting mixturewas stirred at rt for 5 h. After concentration, the crude product waspurified by flash chromatography (silica gel, 40% ethyl acetate inhexanes, then 2% to 6% MeOH in CH₂Cl₂) to give crudecis-adamantane-2-spiro-3′-8′-[(4′-pyridinyloxy)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(eluted first) and pure trioxolane OZ302 (85 mg, 23%, eluted second) asa colorless solid. The crudecis-adamantane-2-spiro-3′-8′-[(4′-pyridinyloxy)methyl]-1′,2′,4′-trioxaspiro[4.5]decanewas disolved in CH₂Cl₂/ether (1:3, 8 ml) and treated with a solution ofmethanesulfonic acid (77 mg, 0.8 mmol) in ether (2 ml). The precipitatewas collected by filtration to afford trioxolane OZ301 (172 mg, 37%) asa colorless solid. For OZ301: mp 153-155° C.; ¹H NMR (500 MHz, CDCl₃) δ1.34-1.49 (m, 2H), 1.61-2.09 (m, 21H), 2.88 (s, 3H), 4.08 (d, J=6.3 Hz,2H), 7.29 (d, J=7.3 Hz, 2H), 8.72 (d, J=6.8 Hz, 2H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.41, 26.48, 26.81, 33.46, 34.76, 35.60, 36.36, 36.71, 39.34,74.77, 108.08, 111.66,112.64, 143.28, 171.01. Anal. Calcd forC₂₃H₃₃NO₇S: C, 59.08; H, 7.11; N, 3.00. Found: C, 58.89; H, 7.15; N,3.09.

[0304]cis-Adamantane-2-spiro-3′-8′-[(4′-oxo-1′(4′H)-pyridinyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ302). For the preparation of OZ302, see OZ301. mp 138-140° C.; ¹H NMR(500 MHz, CDCl₃) δ 1.17-1.35 (m, 2H), 1.59-2.03 (m, 21H), 3.60 (d, J=7.3Hz, 2H), 6.39 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.3 Hz, 2H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.40, 26.79, 27.33, 33.34, 34.74, 36.33, 36.69, 37.66,62.30, 107.90, 111.77, 118.67, 139.88, 178.82. Anal. Calcd forC₂₂H₂₉NO₄.0.25CH₂Cl₂: C, 68.05; H, 7.57; N, 3.57. Found: C, 67.74; H,7.37; N, 3.69.

[0305]cis-Adamantane-2-spiro-3′-8′-[(4′-formyl-1′-piperazinyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ303). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), 1-piperazinecarboxaldehyde (114 mg, 1.0 mmol), and aceticacid (60 mg, 1.0 mmol) in 1,2-dichloroethane (10 ml) under N₂ wasstirred at rt for 10 min before sodium triacetoxyborohydride (322 mg,1.5 mmol) was added. The resulting mixture was stirred at rt for 4 h andthen quenched with saturated aq. NaHCO₃ (15 ml). The organic layer wasseparated and the aqueous layer was extracted with CH₂Cl₂ (2×10 ml). Thecombined organic extracts were washed with water and brine, dried overMgSO₄, and concentrated. The crude product was triturated inhexanes/ether (2:1) to afford trioxolane OZ303 (240 mg, 61%) as acolorless solid. mp 140-142° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.08-1.25 (m,2H), 1.42-2.07 (m, 21H), 2.16 (d, J=7.3 Hz, 2H), 2.35 (t, J=5.7 Hz, 2H),2.39 (t, J=5.2 Hz, 2H), 3.36 (t, J=4.9 Hz, 2H), 3.54 (t, J=4.9 Hz, 2H),8.01 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.48, 26.87, 28.50, 33.58,33.99, 34.78, 34.80, 36.38, 36.79, 40.02, 45.69, 52.79, 54.19, 64.25,108.98, 111.28, 160.67. Anal. Calcd for C₂₂H₃₄N₂O₄: C, 67.66; H, 8.78;N, 7.17. Found: C, 67.85; H, 8.62; N, 7.35.

[0306]cis-Adamantane-2-spiro-3′-8′-[[(2′-pyridinylcarbonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ304). To a mixture of picolinic acid (148 mg, 1.2 mmol), EDCI (290mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF (10 ml) under N₂ wasadded a solution of OZ209 (389 mg, 1.0 mmol) and triethylamine (101 mg,1.0 mmol) in DMF (5 ml). The reaction mixture was stirred at rt for 16 hbefore removal of the solvents. The crude product was dissolved inCH₂Cl₂ (100 ml), washed with water and brine, dried over MgSO₄, andconcentrated. Crystallization of the residue from acetone/water (1:4)gave trioxolane OZ304 (90 mg, 23%) as a colorless solid. mp 130-133° C.;¹H NMR (500 MHz, CDCl₃) δ 1.19-1.45 (m, 2H), 1.57-2.09 (m, 21H), 3.35(app t, J=6.6 Hz, 2H), 7.42 (ddd, J=8.1,4.4, 1.0 Hz, 1H), 7.85 (ddd,J=7.8,7.8, 1.7 Hz, 1H), 8.15 (br s, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.55(d, J=4.9 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.47, 26.86, 27.87,33.80, 34.78, 36.37, 36.51, 36.79, 44.68, 108.69, 111.34, 122.22,126.09, 137.35, 148.02, 149.94, 164.32. Anal. Calcd for C₂₃H₃₀N₂O₄: C,69.32; H, 7.59; N, 7.03. Found: C, 69.33; H, 7.45; N, 6.86.

[0307]cis-Adamantane-2-spiro-3′-8′-[[[(2′-aminoethyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ305). To a solution of the OZ78 active ester (440 mg, 1.0mmol) in CHCl₃ (15 ml) was added rapidly a solution of ethylenediamine(601 mg, 10 mmol) in ethanol (5 ml). The resulting mixture was stirredat rt for 2 h before being quenched with water (20 ml). After separationof the organic layer, the aqueous layer was extracted with CHCl₃ (2×20ml). The combined extracts were washed with water (3×20 ml) and brine(20 ml), dried over MgSO₄, filtered, and concentrated. The residue wasdissolved in CH₂Cl₂ (20 ml) and treated with a solution ofp-toluenesulfonic acid monohydrate (191 mg, 1.0 mmol) in ethanol (2 ml).After evaporation of the solvents, the residue was treated with ether(20 ml), filtered, and washed with ether (20 ml) to afford trioxolaneOZ305 (448 mg, 83%) as a colorless solid. mp 140-142° C.; ¹H NMR (500MHz, CDCl₃) δ 5.91-1.11 (m, 2H), 1.59-2.07 (m, 23H), 2.37 (s, 3H),2.99-3.05 (m, 2H), 3.39-3.44 (m, 2H), 7.16 (d, J=7.8 Hz, 2H), 7.47 (s,1H), 7.69 (d, J=7.8 Hz, 2H), 7.73 (s, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ21.33, 26.48, 26.86, 29.73, 33.08, 33.84, 34.77, 36.37, 36.80, 36.98,40.16, 42.46, 108.44, 111.15, 111.31, 125.73, 129.32, 140.71, 141.33,173.94. Anal. Calcd for C₂₇H₄₀N₂O₇S: C, 60.42; H, 7.51; N, 5.22. Found:C, 60.47; H, 7.47; N, 4.83.

[0308]cis-Adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-oxoethyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ306). To a solution of glycinamide hydrochloride (221 mg, 2.0 mmol),triethylamine (304 mg, 3 mmol), ethanol (5 ml), and water (1 ml) inCHCl₃ (10 ml) was added the OZ78 active ester (440 mg, 1.0 mmol). Theresulting mixture was stirred at rt for 17 h before being diluted withCHCl₃ (20 ml) and water (40 ml). After separation of the organic layer,the aqueous layer was extracted with CHCl₃ (3×10 ml). The combinedextracts were washed with water (2×20 ml) and brine (2×20 ml), driedover MgSO₄, filtered, and concentrated. The residue was crystallizedfrom 30% aq. ethanol to afford trioxolane OZ306 (284 mg, 75%) as acolorless solid. mp 130-132° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.11-1.38 (m,2H), 1.42-2.07 (m, 21H), 2.15 (d, J=5.4 Hz, 2H), 3.95 (s, 2H), 5.84 (brs, 1H), 6.52 (br s, 1H), 6.73 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.45, 26.84, 29.94, 33.47, 33.88, 34.75, 36.34, 36.77, 42.77, 42.88,108.50, 111.33, 171.40, 172.88. Anal. Calcd for C₂₀H₃₀N₂O₅: C, 63.47; H,7.99; N, 7.40. Found: C, 63.60; H, 8.10; N, 7.53.

[0309]cis-Adamantane-2-spiro-3′-8′-[(methylsulfonyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ307). Step 1. To a solution of sodium thiomethoxide (0.42 g, 6 mmol)in DMF (30 ml) was added dropwise a solution of the methanesulfonate ofOZ119 (1.11 g, 3 mmol) in DMF (10 ml). The mixture was heated at 55° C.for 6 h before removal of the solvent. The residue was dissolved inCH₂Cl₂ (30 ml) and washed with water and brine, dried over MgSO₄,filtered, and concentrated. The crude product was purified by flashchromatography (silica gel, 90% ethyl acetate in hexanes) to affordcis-adamantane-2-spiro-3′-8′-[(methylthio)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(0.35 g, 36%) as a colorless oil. ¹H NMR (200 MHz, CDCl₃) δ 1.15-1.37(m, 2H), 1.50-2.02 (m, 21H), 2.10 (s, 3H), 2.40 (d, J=7.0 Hz, 2H). Step2. To a solution of the above thioether (350 mg, 1.08 mmol) in CH₂Cl₂ (5ml) at 0° C. was added dropwise a solution of 3-chloroperoxybenzoic acid(70% reagent, 790 mg, 3.2 mmol) in CHCl₃/CH₂Cl₂ (1:1, 16 ml). After 2 h,the mixture was allowed to warm up to rt and stirred overnight beforebeing quenched with saturated aq. NaHCO₃ (50 ml). The resulting mixturewas concentrated to 50 ml and filtered. The collected precipitate waspurified by flash chromatography (silica gel, 25% ethyl acetate inhexanes; then 5% MeOH in CH₂Cl₂) to afford trioxolane OZ307. (245 mg,64%) as a colorless solid. mp 118-121° C.; ¹H NMR (500 MHz, CDCl₃) δ1.33-1.52 (m, 2H), 1.59-2.03 (m, 20H), 2.04-2.25 (m, 1H), 2.92 (s, 3H),2.94 (d, J=6.4 Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.43, 26.81,30.15, 30.78, 33.66, 34.75, 36.35, 36.73,42.16, 60.13, 107.72, 111.61.Anal. Calcd for C₁₈H₂₈O₅S: C, 60.65; H, 7.92. Found: C, 60.70; H, 7.75.

[0310]cis-Adamantane-2-spiro-3′-8′-[[(2′-amino-2′-oxoethyl)(methylsulfonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ308). To a solution of OZ256 (220 mg, 0.62 mmol) and triethylamine(202 mg, 2 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added a solution ofmethanesulfonyl chloride (137 mg, 1.2 mmol) in CH₂Cl₂ (2 ml). Thereaction mixture was stirred at rt for 4 h, diluted with CH₂Cl₂ (10 ml),washed with water and brine, dried over MgSO₄, filtered, andconcentrated. The crude product was crystallized from CH₂Cl₂/hexanes(1:4) to afford trioxolane OZ308 (250 mg, 94%) as a colorless solid. mp132-136° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.17-1.35 (m, 2H), 1.59-2.05 (m,21H), 2.96 (s, 3H), 3.12 (d, J=7.3 Hz, 2H), 3.89 (s, 2H), 5.60 (s, 1H),6.17 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44, 26.84, 27.71, 33.55,34.76, 36.36, 36.75, 37.97, 51.56, 54.89, 108.43, 111.44,170.70. Anal.Calcd for C₂₀H₃₂N₂O₆S: C, 56.05; H, 7.53; N, 6.54. Found: C, 56.22; H,7.63; N, 6.71.

[0311]cis-Adamantane-2-spiro-3′-8′-[[(carboxymethyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ309). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (588mg, 2.0 mmol), glycine (2.20 g, 20 mmol), acetic acid (180 mg, 3 mmol),and sodium cyanoborohydride (190 mg, 3 mmol) in methanol (100 ml) underAr was stirred at rt for 16 h. The reaction mixture was concentrated,and the residue was triturated with water (50 ml). The solid wascollected by filtration and washed with water and ether. The solid freebase was suspended in methanol (10 ml), treated with a solution ofmethanesulfonic acid (91 mg, 0.95 mmol) in methanol (2 ml), andconcentrated. The residue was crystallized from MeOH/ether (1:9) toafford trioxolane OZ309 (350 mg, 39%) as a colorless solid. mp 144-146°C.; ¹H NMR (500 MHz, DMSO-d₆).0.97-1.21 (m, 2H), 1.54-2.02 (m, 21H),2.30 (s, 3H), 2.82 (d, J=5.9 Hz, 2H), 3.86 (s, 2H), 8.80 (s, 2H); ¹³CNMR (125.7 MHz, DMSO-d₆) δ 25.97, 26.37, 27.36, 32.59, 32.96, 34.41,34.43, 35.91, 36.23, 47.46, 51.83, 108.21, 110.84, 168.26. Anal. Calcdfor C₂₀H₃₃NO₈S.0.5H₂O: C, 52.61; H, 7.51; N, 3.07. Found: C, 52.27; H,7.49; N, 3.15.

[0312]cis-Adamantane-2-spiro-3′-8′-[[(1′-methyl-1′H-imidazol-2′-yl)sulfonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ310). Step 1. To a suspension of 60% NaH (160 mg, 4 mmol) in DMF (5ml) under N₂ at 0° C. was added dropwise a solution of2-mercapto-1-methylimidazole (456 mg, 4.0 mmol) in DMF (10 ml). Themixture was stirred for 1 h before a solution of the methanesulfonate ofOZ119 (744 mg, 2 mmol) in DMF (4 ml) was added dropwise. The mixture wasstirred at rt overnight and concentrated. The residue was dissolved inCH₂Cl₂ (30 ml), washed with water and brine, dried over MgSO₄, filtered,and concentrated. The crude product was purified by flash chromatography(silica gel, 25% ethyl acetate in hexanes) to affordcis-adamantane-2-spiro-3′-8′-[[(1′-methyl-1′H-imidazol-2′-yl)thio]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(0.24 g, 30%) as a colorless solid. mp 140-142° C. ¹H NMR (200 MHz,CDCl₃), 1.20-1.35 (m, 2H), 1.60-2.00 (m, 21H), 3.00 (d, J=6.8 Hz, 2H),3.60 (s, 3H), 6.90 (s, 1H), 7.03 (s, 1H). Step 2. To a solution of theabove thioether (250 mg, 0.6 mmol) in CH₂Cl₂ (5 ml) at 0° C. was addeddropwise a solution of 3-chloroperoxybenzoic acid (70% reagent, 400 mg,1.6 mmol) in CHCl₃/CH₂Cl₂ (1:1, 8 ml). After 2 h, the mixture wasallowed to warm up to rt, stirred overnight, and concentrated to 3 ml.The residue was diluted with saturated aq. NaHCO₃ (20 ml) and extractedwith CH₂Cl₂ (2×20 ml). The combined extracts were washed with water andbrine, dried over MgSO₄, filtered, and concentrated. The crude productwas purified by flash chromatography (silica gel, 10% to 50% ethylacetate in hexanes) to afford trioxolane OZ310 (130 mg, 51%) as acolorless solid. mp 151-152° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.31-1.51 (m,2H), 1.59-2.04 (m, 20H), 2.06-2.25 (m, 1H), 3.41 (d, J=6.3 Hz, 2H), 3.99(s, 3H), 6.98 (s, 1H), 7.12 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44,26.84, 29.96, 30.89, 33.68, 34.76, 35.08, 36.35, 36.75, 59.99, 107.77,111.55, 125.39, 128.96, 142.61. Anal. Calcd for C₂₁H₃₀N₂O₅S: C, 59.69;H, 7.16; N, 6.63. Found: C, 59.56; H, 7.10; N, 6.47.

[0313]cis-Adamantane-2-spiro-3′-8′-[[[4′-(aminocarbonyl)-1′-piperidinyl]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ311). To a solution of the OZ78 active ester (220 mg, 0.5 mmol) inCHCl₃ (10 ml) and ethanol (10 ml) was added isonipecotamide (128 mg, 1.0mmol). The resulting mixture was stirred at rt for 4 h before removal ofthe solvents. The residue was crystallized from ethanol/water (2:1) toafford trioxolane OZ311 (164 mg, 76%) as a colorless solid. mp 149-151°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.161.32 (m, 2H), 1.58-2.06 (m, 25H), 2.22(d, J=6.8 Hz, 2H), 2.39 (tt, J=11.2, 3.9 Hz, 1H), 2.69 (t, J=11.5 Hz,1H), 3.06 (t, J=11.7 Hz, 1H), 3.92 (d, J=13.7 Hz, 1H), 4.60 (d, J=13.2Hz, 1H), 5.54 (s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.46, 26.84, 28.60,29.02, 30.25, 30.30, 33.31, 34.05, 34.77, 36.37, 36.78, 39.24, 41.04,42.37, 45.15, 108.61, 111.31, 170.39, 176.16. Anal. Calcd forC₂₄H₃₆N₂O₅: C, 66.64; H, 8.39; N, 6.48. Found: C, 66.39; H, 8.46; N,6.30.

[0314]cis-Adamantane-2-spiro-3′-8′-[[(4′-carboxy-1′-piperidinyl)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ312). To a solution of the OZ78 active ester (220 mg, 0.5 mmol),water (5 ml), and ethanol (10 ml) in CHCl₃ (10 ml) was addedisonipecotic acid (129 mg, 1.0 mmol). The resulting mixture was stirredat rt for 16.5 h before removal of the solvents. The residue wascrystallized from ethanol/water (1:1) to afford trioxolane OZ312 (179mg, 82%) as a colorless solid. mp 159-161° C.; ¹H NMR (500 MHz, CDCl₃) δ1.18-1.35 (m, 2H), 1.58-2.06 (m, 25H), 2.24 (d, J=6.8 Hz, 2H), 2.60 (tt,J=10.7, 3.9 Hz, 1H), 2.86 (t, J=11.2 Hz, 1H), 3.14 (t, J=11.2 Hz, 1H),3.85 (d, J=13.7 Hz, 1H), 4.44 (d, J=13.6 Hz, 1H); ¹³C NMR (125.7 MHz,CDCl₃).26.48, 26.86, 27.72, 28.33, 30.27, 33.37, 34.06, 34.79, 36.39,36.80, 39.23, 40.46, 40.93, 44.96, 108.62, 111.34, 170.53, 178.19. Anal.Calcd for C₂₄H₃₅NO₆: C, 66.49; H, 8.14; N, 3.23. Found: C, 66.28; H,8.26; N, 3.13.

[0315]cis-Adamantane-2-spiro-3′-8′-[[[[2′-(4′-morpholinyl)ethyl]amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ313). To a solution of the OZ78 active ester (220 mg, 0.5mmol) in CHCl₃ (10 ml) was added a solution of4-(2-aminoethyl)morpholine (130 mg, 1.0 mmol) in CHCl₃ (1 ml). Theresulting mixture was stirred at rt for 2 h before being quenched withwater (20 ml). After separation of the organic layer, the aqueous layerwas extracted with CHCl₃ (2×20 ml). The combined extracts were washedwith water (3×20 ml) and brine (20 ml), dried over MgSO₄, and filtered.To the filtrate was added a solution of p-toluenesulfonic acidmonohydrate (76 mg, 0.4 mmol) in ethanol (1 ml). After evaporation ofthe solvents, the residue was treated with ether (20 ml), filtered, andwashed with ether (20 ml) to afford trioxolane OZ313 (191 mg, 62%) as acolorless solid. mp 130-132° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.07-1.29 (m,2H), 1.55-2.04 (m, 21H), 2.08 (d, J=7.3 Hz, 2H), 2.39 (s, 3H), 2.81-3.05(m, 2H), 3.27-3.42 (m, 2H), 3.61-3.82 (m, 4H), 3.89-4.09 (m, 4H), 7.23(d, J=7.8 Hz, 2H), 7.75 (d, J=7.8 Hz, 2H), 7.94 (br s, 1H), 10.56 (br s,1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 1.33, 26.46, 26.85, 29.77, 33.19,33.53, 33.90, 34.76, 36.35, 36.78, 42.38, 52.73, 57.20, 63.67, 108.48,111.17, 125.82, 129.14, 140.96, 174.20. Anal. Calcd forC₃₁H₄₆N₂O₈S.0.5H₂O: C, 60.47; H, 7.69; N, 4.55. Found: C, 60.26; H,8.03; N, 4.36.

[0316]cis-Adamantane-2-spiro-3′-8′-[[[4′-(2′-pyrimidinyl)-1′-piperazinyl]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ314). To a solution of the OZ78 active ester (220 mg, 0.5 mmol) inCHCl₃ (10 ml) was added a solution of 1-(2-pyrimidyl)piperazine (164 mg,1.0 mmol) in CHCl₃ (10 ml). The resulting mixture was stirred at rt for2 h before removal of the solvent. The residue was crystallized fromethanol to afford trioxolane OZ314 (199 mg, 85%) as a colorless solid.mp 160-162° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.18-1.35 (m, 2H), 1.58-2.08(m, 21H), 2.27 (d, J=6.8 Hz, 2H), 3.54 (t, J=5.2 Hz, 2H), 3.71 (t, J=5.2Hz, 2H), 3.73-3.89 (m, 4H), 6.54 (dd, J=4.9, 4.9 Hz, 1H), 8.33 (d, J=4.4Hz, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.47, 26.85, 30.30, 33.32, 34.06,34.77, 36.37, 36.79, 39.31, 41.40, 43.60, 43.81, 45.51, 108.60, 110.46,111.32, 157.76, 161.51, 170.73. Anal. Calcd for C₂₆H₃₆N₄O₄: C, 66.64; H,7.74; N, 11.96. Found: C, 67.03; H, 8.25; N, 11.84.

[0317]cis-Adamantane-2-spiro-3′-8′-[[[(trans-4′-aminocyclohexyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ315). To a solution of the OZ78 active ester (220 mg, 0.5mmol) in CHCl₃ (10 ml) was added rapidly a solution oftrans-1,4-diaminocyclohexane (343 mg, 3.0 mmol) in CHCl₃ (10 ml). Theresulting mixture was stirred at rt for 1 h and filtered. The filtratewas diluted with water (30 ml). After separation of the organic layer,the aqueous layer was extracted with CHCl₃ (2×10 ml). The combinedextracts were washed with water (2×20 ml) and brine (20 ml), dried overMgSO₄, and filtered. To the filtrate was added a solution ofp-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) in ethanol (1 ml).After evaporation of the solvents, the residue was treated with ether(20 ml), filtered, and washed with ether (20 ml) to afford trioxolaneOZ315 (139 mg, 47%) as a colorless solid. mp 140° C. dec; ¹H NMR (500MHz, DMSO-d₆) δ 0.97-1.43 (m, 6H), 1.54-2.02 (m, 27H), 2.29 (s, 3H),2.84-3.06 (m, 1H), 3.38-3.52 (m, 1H), 7.12 (d, J=7.8 Hz, 2H), 7.48 (d,J=7.8 Hz, 2H), 7.71 (s, 1H), 7.73 (s, 3H); ¹³C NMR (125.7 MHz, DMSO-d₆)δ 20.95, 25.97, 26.37, 29.26, 29.57, 30.16, 33.03, 33.58, 34.42, 35.92,36.25, 42.10, 46.60, 48.75, 108.57, 110.63, 125.65, 128.25, 137.87,145.76, 170.48. Anal. Calcd for C₃₁H₄₆N₂O₇S: C, 63.02; H, 7.85; N, 4.74.Found: C, 62.88; H, 7.68; N, 4.57.

[0318]cis-Adamantane-2-spiro-3′-8′-[[2′-[(3′-pyridinylcarbonyl)amino]acetyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ316). To a solution of nicotinoylglycine (216 mg, 1.2 mmol),EDCI (290 mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF (10 ml)under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at rt for 16 h before being quenched with water (70 ml) and1 M aq. NaOH (3 ml). The precipitate was collected by filtration,re-dissolved in CH₂Cl₂ (4 ml), and treated with a solution ofmethanesulfonic acid (94 mg, 0.98 mmol) in ether (12 ml). Theprecipitate was obtained by filtration to afford trioxolane OZ316 (420mg, 76%) as a colorless solid. mp 142-145° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 0.95-1.23 (m, 2H), 1.41-1.97 (m, 21H), 2.38 (s, 3H), 2.94 (app t,J=6.3 Hz, 2H), 3.91 (d, J=5.3 Hz, 2H), 7.96 (br s, 1H), 8.02 (dd, J=5.9,5.9 Hz, 1H), 8.69 (d, J=7.3 Hz, 1H), 8.94 (d, J=5.3 Hz, 1H), 9.19 (s,1H), 9.22 (t, J=5.6 Hz, 1H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 26.00,26.40, 27.63, 33.43, 34.44, 35.84, 35.94, 36.27, 42.82, 43.94, 108.76,110.66, 125.99, 131.79, 141.26, 144.34, 147.12, 163.32, 168.40. Anal.Calcd for C₂₆H₃₇N₃O₈S: C, 56.61; H, 6.76; N, 7.62. Found: C, 56.51; H,6.60; N, 7.56.

[0319]cis-Adamantane-2-spiro-3′-8′-[[[(1′-aminocyclopentyl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ317).

[0320] To a solution of 1-amino-1-cyclopentanecarboxylic acid (155 mg,1.2 mmol), EDCI (290 mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF(10 ml) under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at rt for 16 h before being quenched with water (70 ml) and3 M aq. NaOH (2 ml). The precipitate was collected by filtration andtriturated with 50% aq. ethanol to afford trioxolane OZ317 (250 mg, 62%)as a colorless solid. mp 160-162° C. (50% aq. ethanol); ¹H NMR (500 MHz,CDCl₃) δ 1.15-1.33 (m, 2H), 1.38-2.07 (m, 27H), 2.19-2.29 (m, 2H), 3.12(app t, J=6.6 Hz, 2H), 7.90 (br s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.47, 26.86, 27.55, 33.60, 34.78, 34.79, 36.38, 36.77, 40.36, 48.54,108.40, 111.50. Anal. Calcd for C₂₃H₃₆N₂O₄: C, 68.29; H, 8.97; N, 6.92.Found: C, 68.47; H, 8.70; N, 6.72.

[0321]cis-Adamantane-2-spiro-3′-8′-[[(3′-ethoxy-3′-oxopropyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ318). To a mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), β-alanine ethyl ester hydrochloride (154 mg, 1.0 mmol),and triethylamine (101 mg, 1.0 mmol) in 1,2-dichloroethane (15 ml) at rtunder N₂ was added sodium triacetoxyborohydride (322 mg, 1.5 mmol). Theresulting mixture was stirred at rt for 4 h, and then quenched withsaturated aq. NaHCO₃ (20 ml) and 1 M. aq. NaOH (3 ml). The organic layerwas separated, and the aqueous layer was extracted with CH₂Cl₂ (2×20ml). The combined organic extracts were washed with water and brine,dried over MgSO₄, and concentrated. The crude product was dissolved inCH₂Cl₂ (2 ml) and added to a solution of p-toluenesulfonic acidmonohydrate (170 mg, 0.89 mmol) in ether/CH₂Cl₂ (4:1, 5 ml). Hexanes (10ml) was added, and the resulting solid was collected by filtration toafford trioxolane OZ318 (220 mg, 39%) as a colorless solid. mp 128-131°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.10-1.23 (m, 2H), 1.24 (t, J=7.1 Hz, 3H),1.45-2.07 (m, 21H), 2.37 (s, 3H), 2.76-2.85 (m, 2H), 2.96 (app t, J=7.1Hz, 2H), 3.25-3.34 (m, 2H), 4.13 (q, J=7.0 Hz, 2H), 7.20 (d, J=8.3 Hz,2H), 7.71 (d, J=7.8 Hz, 2H), 8.60 (s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ14.05, 21.28, 26.43, 26.84, 27.66, 30.22, 33.04, 33.11, 34.73, 36.34,36.74, 44.08, 53.62, 61.28, 107.91, 111.33, 125.78, 128.98, 140.61,141.54, 170.62. Anal. Calcd for C₂₉H₄₃NO₈S: C, 61.57; H, 7.66; N, 2.48.Found: C, 61.79; H, 7.53; N, 2.50.

[0322]cis-Adamantane-2-spiro-3′-8′-[[(3′-amino-3′-oxopropyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ319). A mixture of β-alaninamide hydrochloride (375 mg, 3mmol),cis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1 mmol), and NaBH₃CN (100 mg, 1.5 mmol) in methanol (15 ml) wasstirred at rt for 2 days and then concentrated. The crude product wastriturated with 0.5 M aq. NaOH, and the resulting solid was crystallizedfrom ether/CH₂Cl₂ (9:1) to afford the trioxolane free amine (200 mg,55%). To a solution of methanesulfonic acid (50 mg, 0.51 mmol) in ether(5 ml) was added a solution of the above free amine (179 mg, 0.49 mmol)in CH₂Cl₂ (2 ml). The solid was collected by filtration, washed withether, and dried to afford trioxolane OZ319 (190 mg, 84%) as a colorlesssolid. mp 133-136° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.22-1.38 (m, 2H),1.61-2.05 (m, 21H), 2.75 (s, 3H), 2.81-2.96 (m, 4H), 3.25 (br s, 2H),6.76 (s, 1H), 7.58 (s, 1H), 8.59 (br s, 2H); ¹³C NMR (125.7 MHz, CDCl₃)δ 26.43, 26.83, 27.57, 30.54, 33.28, 33.34, 34.76, 36.36, 36.74, 39.49,44.94, 53.42, 107.89, 111.59, 173.76. Anal. Calcd for C₂₁H₃₆N₂O₇S: C,54.76; H, 7.88; N, 6.08. Found: C, 54.60; H, 7.61; N, 6.06.

[0323]cis-Adamantane-2-spiro-3′-8′-(4′-aminocarbonyl-1′H-imidazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ320). To a mixture of OZ225(cis-Adamantane-2-spiro-3′-8′-(4′-carboxy-1′H-imidazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane) (600 mg, 1.54mmol), Boc₂O (375 mg, 2.02 mmol), ammonium bicarbonate (156 mg, 1.92mmol) in acetonitrile (60 ml) under N₂ was slowly added pyridine (75 mg,0.95 mmol). After completion of the addition, the reaction mixture wasstirred at rt for 16 h before concentration. The crude product wasdissolved in CH₂Cl₂ (50 ml), washed with water and brine, dried overMgSO₄, and concentrated to afford the corresponding anhydride of OZ225(560 mg). A mixture of the above anhydride and ammonia (7 N in methanol,3 ml) in CH₂Cl₂ (10 ml) was stirred at rt overnight and then filtered.The filtrate was concentrated and triturated with CH₂Cl₂/ether (1:2).The resulting solid was collected by filtration and dried to affordtrioxolane OZ320 (250 mg, 42%) as a colorless solid. mp 152-155° C.; ¹HNMR (500 MHz, CDCl₃) δ 1.19-1.34 (m, 2H), 1.54-2.07 (m, 21H), 3.81 (d,J=7.3 Hz, 2H), 5.46 (br s, 1H), 6.96 (s, 1H), 7.36 (s, 1H), 7.56 (s,1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.43, 26.82, 27.52, 33.40, 34.76,36.34, 36.73, 37.66, 52.98, 108.06, 111.68, 122.65, 136.80, 137.06,164.62. Anal. Calcd for C₂₁H₂₉N₃O₄.0.1CH₂Cl₂: C, 64.00; H, 7.43; N,10.61. Found: C, 64.26; H, 7.13; N, 10.34.

[0324] cis-Adamantane-2-spiro-3′-8′-(5′-aminocarbonyl-1′H-imidazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane (OZ321). To amixture of OZ231(cis-Adamantane-2-spiro-3′-8′-(5′-carboxy-1′H-imidazol-1′-ylmethyl)-1′,2′,4′-trioxaspiro[4.5]decane)(350 mg, 0.9 mmol), Boc₂O (275 mg, 1.26 mmol), and ammonium bicarbonate(92 mg, 1.17 mmol) in DMF (2 ml) under N₂ was slowly added pyridine (50mg, 0.6 mmol). After completion of the addition, the reaction mixturewas stirred at rt for 16 h before ammonia (7 N in methanol, 1 ml) wasadded. The resulting mixture was stirred for 3 h and concentrated. Thecrude product was dissolved in CH₂Cl₂ (30 ml), washed with water andbrine, dried over MgSO₄, and concentrated. Crystallization from 40% aq.ethanol/NEt₃ (9:1) afforded trioxolane OZ321 (50 mg, 14%) as a colorlesssolid. mp 148-150° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.18-1.32 (m, 2H),1.54-2.07 (m, 21H), 4.18 (d, J=8.3 Hz, 2H), 5.68 (br s, 2H), 7.50 (s,1H), 7.51 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44, 26.83, 27.46,33.49, 34.75, 36.35, 36.75, 37.03, 52.10, 108.39, 111.47, 124.40,133.22, 142.17, 161.66. Anal. Calcd for C₂₁H₂₉N₃O₄.0.5H₂O: C, 63.62; H,7.63; N, 10.60. Found: C, 63.58; H, 7.68; N, 10.28.

[0325]cis-Adamantane-2-spiro-3′-8′-[[[2′-(formylamino)acetyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ322). To a solution of N-formylglycine (124 mg, 1.2 mmol), EDCI (290mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF (10 ml) under N₂ wasadded a solution of OZ209 (389 mg, 1.0 mmol) and triethylamine (101 mg,1.0 mmol) in DMF (5 ml). The resulting mixture was stirred at rt for 16h before being quenched with water (70 ml). The precipitate wascollected by filtration and recrystallized from hexane/CH₂Cl₂ (4:1) toafford trioxolane OZ322 (270 mg, 71%) as a colorless solid. mp 125-129°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.33 (m, 2H), 1.45-2.07 (m, 21H),3.14 (app t, J=6.4 Hz, 2H), 3.98 (d, J=4.9 Hz, 2H), 6.52 (s, 1H), 6.77(s, 1H), 8.23 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.44, 26.84, 27.68,33.68, 34.76, 36.19, 36.35, 36.75, 41.85, 44.86, 108.51, 111.40, 161.50,168.26. Anal. Calcd for C₂₀H₃₀N₂O₅: C, 63.47; H, 7.99; N, 7.40. Found:C, 63.55; H, 8.02; N, 7.27.

[0326]cis-Adamantane-2-spiro-3′-8′-[4′-(2′-aminoethoxy)phenyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ323). Step 1. To a solution of OZ288 (1.07 g, 3 mmol),triphenylphosphine (1.26 g, 4.8 mmol), N-(2-hydroxyethyl)phthalimide(0.86 g, 4.5 mmol) in THF (20 ml) at 0° C. was added dropwisediisopropyl azodicarboxylate (0.98 g, 4.8 mmol). The mixture was stirredat rt for 36 h and concentrated. The residue was purified by flashchromatography (silica gel, 10% ethyl acetate in hexanes) followed bycrystallization from ethanol/triethylamine (4:1) to afford the desiredphthalimide derivative (180 mg, 12%) as a colorless solid. mp 142-144°C.; ¹H NMR (500 MHz, CDCl₃) □ 1.62-2.02 (m, 22H), 2.43-2.48 (m, 1H),4.09 (t, J=5.9 Hz, 2H), 4.20 (t, J=5.9 Hz, 2H), 6.80 (d, J=8.3 Hz, 2H),7.07 (d, J=8.3 Hz, 2H), 7.71-7.73 (m, 2H), 7.84-7.86 (m, 2H). Step 2. Amixture of above phthalimide derivative (180 mg, 0.34 mmol) andhydrazine monohydrate (140 mg, 2.5 mmol) in chloroform/ethanol (7:3, 10ml) was heated at 55-60° C. for 24 h. After being cooled to rt, thesolid by-product was filtered off. The filtrate was diluted with CHCl₃(10 ml), washed with water (2×20 ml) and brine (20 ml), dried overMgSO₄, and concentrated. The residue was dissolved in ether (4 ml) andthen a solution of methanesulfonic acid (34 mg, 0.35 mmol) in ether (4ml) was added. The solid was collected by filtration to affordtrioxolane OZ323 (118 mg, 70%) as a colorless solid. mp 152-155° C.; ¹HNMR (500 MHz, CDCl₃) δ 1.55-2.07 (m, 22H), 2.47 (t, J=12.0 Hz, 1H), 2.67(s, 3H), 3.28-3.33 (m, 2H), 4.11 (s, 2H), 6.83 (d, J=8.3 Hz, 2H), 7.07(d, J=8.8 Hz, 2H), 7.73 (s, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.50,26.90, 31.62, 34.69, 34.81, 36.42, 36.82, 39.18, 39.43, 41.99, 63.92,108.34, 111.35, 114.71, 127.74, 139.44, 156.18. Anal. Calcd forC₂₅H₃₇NO₇S.0.17CH₂Cl₂: C, 59.29; H, 7.38; N, 2.75. Found: C, 59.49; H,7.06; N, 2.81.

[0327]cis-Adamantane-2-spiro-3′-8′-[[(1′-oxido-2′-pyridinyl)sulfonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ324). To a solution of OZ328 (280 mg, 0.69 mmol) in CH₂Cl₂ (5 ml) at0° C. was added dropwise a solution of 3-chloroperoxybenzoic acid (70%reagent, 400 mg, 1.6 mmol) in CHCl₃/CH₂Cl₂ (1:1, 8 ml). After 2 h ofstirring, the mixture was allowed to warm up to rt and stirred overnightbefore being diluted with saturated aq. NaHCO₃ (50 ml). The mixture wasstirred for additional 1.5 h. The aqueous layer was extracted with CHCl₃(3×15 ml). The combined organic solutions were washed with water andbrine, dried over MgSO₄, filtered, and concentrated. The crude productwas triturated with ether/hexanes (1:1, 10 ml) to afford trioxolaneOZ324 (150 mg, 50%) as a colorless solid. mp 148-151° C.; ¹H NMR (500MHz, CDCl₃) δ 1.35-1.52 (m, 2H), 1.53-2.22 (m, 21H), 3.65 (d, J=6.8 Hz,2H), 7.44 (ddd, J=7.8, 7.8, 1.0 Hz, 1H), 7.51 (ddd, J=6.8, 6.8, 2.0 Hz,1H), 8.10 (dd, J=8.1, 1.8 Hz, 1H), 8.27 (d, J=6.3 Hz, 1H); ¹³C NMR(125.7 MHz, CDCl₃) δ 26.43, 26.83, 29.91, 30.95, 33.64, 34.75, 34.76,36.34, 36.74, 58.48, 107.73, 111.54,125.39,127.57, 129.67,141.15,147.35.Anal. Calcd for C₂₂H₂₉NO₆S: C, 60.67; H. 6.71; N, 3.22. Found: C, 60.51;H, 6.63; N, 3.11.

[0328]cis-Adamantane-2-spiro-3′-8′-[(2′-pyrimidinyloxy)methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ325). To a suspension of 60% NaH (80 mg, 2 mmol) in DMF (10ml) under N₂ at 0° C. was added dropwise a solution of OZ119 (588 mg, 2mmol) in DMF (20 ml). The mixture was stirred at rt for 1 h and cooleddown to 0° C. After 2-chloropyrimidine (241 mg, 2 mmol) was added, theresulting mixture was stirred at rt overnight. Water (70 ml) was added,and the precipitate was collected by filtration. The crude product wasdissolved in ether (20 ml) and added to a solution of methanesulfonicacid (170 mg, 1.77 mmol) in ether/CH₂Cl₂ (1:1, 4 ml). The solid wascollected by filtration and dried to afford trioxolane OZ325 (530 mg,57%) as a colorless solid. mp 133-135° C.; ¹H NMR (500 MHz, CDCl₃) δ1.27-1.41 (m, 2H), 1.62-2.04 (m, 21H), 2.93 (s, 3H), 4.42 (d, J=7.4 Hz,2H), 7.31-7.36 (m, 1H), 8.94 (d, J=5.4 Hz, 2H), 11.28 (br s, 1H); ¹³CNMR (125.7 MHz, CDCl₃) δ 26.45, 26.51, 26.84, 33.40, 34.77, 35.29,36.37, 36.75, 39.28, 74.65, 108.31, 111.55, 115.16, 159.43, 160.34.Anal. Calcd for C₂₂H₃₂N₂O₇S: C, 56.39; H, 6.88; N. 5.98. Found: C,56.16; H, 6.72; N, 5.89.

[0329]cis-Adamantane-2-spiro-3′-8′-[(2′-pyrimidinylamino)methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ326). A mixture of OZ209 (389 mg, 1 mmol), triethylamine (101 mg, 1mmol), K₂CO₃ (276 mg, 2 mmol), and 2-chloropyrimidine (170 mg, 1.5 mmol)in DMF (15 ml) was heated at 50° C. for 20 h. The mixture was cooled tort and diluted with water (70 ml). The precipitate was collected andtriturated with ether/hexanes (1:1, 10 ml). The filtrate wasconcentrated, and the residue was purified by flash chromatography(silica gel, 1%-5% methanol in CH₂Cl₂) to afford trioxolane OZ326 (75mg, 20%) as a colorless solid. mp 112-115° C.; ¹H NMR (500 MHz, CDCl₃) δ1.15-1.35 (m, 2H), 1.55-2.07 (m, 21H), 3.29 (app t, J=6.6 Hz, 2H), 5.23(s, 1H), 6.51 (t, J=4.9 Hz, 1H), 8.26 (d, J=4.4 Hz, 2H); ¹³C NMR (125.7MHz, CDCl₃) δ 26.47, 26.87, 27.86, 33.82, 34.78, 34.80,36.26,36.38,36.80, 46.71, 108.81, 110.46, 111.31, 158.00, 162.48. Anal.Calcd for C₂₁H₂₉N₃O₃: C, 67.90; H, 7.87; N, 11.31. Found: C, 67.82; H,7.82; N, 11.26.

[0330]cis-Adamantane-2-spiro-3′-8′-[[(2′S)-2′-aminocarbonyl-1′-pyrrolidinyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate(OZ327). A mixture ofcis-adamantane-2-spiro-3′-8′-formyl-1′,2′,4′-trioxaspiro[4.5]decane (292mg, 1.0 mmol), L-prolinamide (342 mg, 3.0 mmol), and NaBH₃CN (100 mg,1.5 mmol) in methanol (20 ml) was stirred at rt overnight before removalof the solvent. The residue was diluted with saturated aq. NaHCO₃ (30ml) and extracted with CHCl₃ (3×25 ml). The combined organic extractswere washed with water and brine, dried over MgSO₄, and concentrated.The crude product was dissolved in ethanol (10 ml) and added to asolution of p-toluenesulfonic acid monohydrate (570 mg, 3 mmol) in 50%aq. ethanol (20 ml). Water (10 ml) was added, and the resultingprecipitate was collected by filtration to afford trioxolane OZ327 (235mg, 42%) as a colorless solid. mp 171-173° C.; ¹H NMR (500 MHz, CDCl₃) δ1.03-1.22 (m, 2H), 1.51-1.94 (m, 23H), 1.95-2.06 (m, 1H), 2.28 (s, 3H),2.32-2.44 (m, 1H), 3.01 (app t, J=5.9 Hz, 2H), 3.05-3.19 (m, 1H),3.60-3.75 (m, 1H), 4.04 (app q, J=8.1 Hz, 1H), 7.10 (d, J=8.3 Hz, 2H),7.46 (d, J=7.8 Hz, 2H), 7.81 (s, 1H), 8.05 (s, 1H), 8.96 (s, 1H); ¹³CNMR (125.7 MHz, CDCl₃) δ 520.94, 22.58, 25.96, 26.36, 26.59, 27.34,27.67, 28.93, 32.39, 32.80, 33.00, 34.40, 35.89, 36.22, 54.77, 59.92,67.78, 108.10, 110.85, 125.65, 128.20, 137.72, 145.98, 169.15. Anal.Calcd for C₂₉H₄₂N₂O₇S: C, 61.90; H, 7.52; N, 4.98. Found: C, 62.07; H,7.42; N, 4.70.

[0331]cis-Adamantane-2-spiro-3′-8′-[[(1′-oxido-2′-pyridinyl)thio]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ328). To a solution of 2-mercaptopyridine-N-oxide sodium salt hydrate(0.68 g, 4.0 mmol) in DMF (20 ml) was added dropwise a solution of themethanesulfonate of OZ119 (0.8 g, 1.8 mmol) in DMF (5 ml). The mixturewas stirred at 50-60° C. overnight and then concentrated. The residuewas triturated sequentially with water, ether, and then 80% aq. ethanol.The solid was collected by filtration and dried to afford trioxolaneOZ328 (0.25 g, 34%) as a colorless solid. mp 151-153° C.; ¹H NMR (500MHz, CDCl₃) δ 1.31-1.47 (m, 2H), 1.59-2.07 (m, 21H), 2.78 (d, J=6.8 Hz,2H), 7.04 (dd, J=6.3, 6.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.24 (dd,J=7.8, 7.8 Hz, 1H), 8.26 (d, J=6.4 Hz, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.45, 26.84, 30.01, 33.81, 34.76, 35.46, 36.37, 36.55, 36.75, 108.29,111.51, 120.15, 121.25, 125.58, 138.80, 152.58. Anal. Calcd forC₂₂H₂₉NO₄S: C, 65.48; H, 7.24; N, 3.47. Found: C, 65.40; H, 7.07; N,3.56.

[0332]cis-Adamantane-2-spiro-3′-8′-[[(1′-piperazinylcarbonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ329). Step 1. A mixture of OZ209 (2.0 g, 5.0 mmol),pyridine (0.8 g, 10 mmol), 4-nitrophenyl chloroformate (2.02 g, 10 mmol)in CH₂Cl₂ (60 ml) was refluxed for 4.5 h, cooled to rt, and then dilutedwith CH₂Cl₂ (80 ml). The solution was washed with water and brine, driedover MgSO₄, filtered, and concentrated. The crude product was purifiedby flash chromatography (silica gel, 0-1% methanol in CH₂Cl₂) to affordthe desired carbamate (1.36 g, 59%) as a colorless solid. mp 135-138°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.23-1.33 (m, 2H), 1.58-2.00 (m, 21H),3.17 (t, J=6.3 Hz, 2H), 5.17 (br s, 1H), 7.31 (d, J=9.3 Hz, 2H), 8.24(d, J=9.3 Hz, 2H). Step 2. A mixture of above carbamate (0.61 g, 1.3mmol) and piperazine (1.15 g, 13 mmol) in CHCl₃ (10 ml) was stirred atrt for 2 h. The reaction mixture was diluted with CHCl₃ (25 ml), washedwith water, 0.25 M aq. NaOH, water, and brine, dried over MgSO₄,filtered, and concentrated. The crude product was dissolved in ether (10ml) and added to a solution of p-toluenesulfonic acid monohydrate (380mg, 2 mmol) in methanol/CH₂Cl₂ (1:10, 11 ml). Ether (30 ml) was added.The precipitate was collected and dried to afford trioxolane OZ329 (530mg, 71%) as a colorless solid. mp 165-167° C.; ¹H NMR (500 MHz, DMSO-d₆)50.91-1.09 (m, 2H), 1.32-1.97 (m, 21H), 2.28 (s, 3H), 2.87 (app t, J=6.1Hz, 2H), 3.04 (br s, 4H), 3.46 (t, J=5.2 Hz, 4H), 6.71 (t, J=5.4 Hz,1H), 7.11 (d, J=7.8 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 8.64 (s, 2H); ¹³CNMR (125.7 MHz, DMSO-d₆) δ 20.96, 25.99, 26.40, 27.70, 33.48, 34.43,35.94, 36.07, 36.27, 40.75, 42.84, 45.57, 108.87, 110.64, 125.67,128.28, 137.91, 145.73, 157.19. Anal. Calcd for C₂₉H₄₃N₃O₇S: C, 60.29;H, 7.50; N, 7.27. Found: C, 60.37; H, 7.34; N, 7.19.

[0333]cis-Adamantane-2-spiro-3′-8′-[[[(3′-amino-2′-pyrazinyl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ330). To a solution of 3-amino-pyrazine-2-carboxylic acid (167 mg,1.2 mmol), EDCI (290 mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF(10 ml) under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at rt for 16 h before being quenched with water (70 ml). Theprecipitate was collected by filtration, triturated with ether/hexanes(1:1), and crystallized from 95% aq. ethanol to afford trioxolane OZ330(86 mg, 21%) as a colorless solid. mp 128-131° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.21-1.39 (m, 2H), 1.51-2.07 (m, 21H), 3.29 (app t, J=6.4 Hz,2H), 7.78 (d, J=2.5 Hz, 1H), 7.99 (br s, 1H), 8.14 (d, J=2.5 Hz, 1H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.47, 26.87, 27.86, 33.78, 34.79, 36.38,36.50, 36.79, 44.44, 108.63, 111.39, 126.61, 131.58, 146.58,155.04,166.04. Anal Calcd for C₂₂H₃₀N₄O₄00.17CH₂Cl₂: C, 62.11; H, 7.13; N,13.07. Found: C, 61.86; H, 6.98; N, 13.40.

[0334]cis-Adamantane-2-spiro-3′-8′-[[(1′-methyl-1′H-tetrazol-5′-yl)thio]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ331). To a solution of 1-methyl-5-mercaptotetrazole, sodium saltdihydrate (0.70 g, 4.0 mmol) in DMF (20 ml) was added a solution of themethanesulfonate of OZ119 (0.90 g, 2.0 mmol) in DMF (5 ml). The mixturewas stirred at 50-60° C. overnight and then concentrated. The residuewas triturated with water, and the resulting solid was purified byrepeated flash chromatography (silica gel, hexanes/ethyl acetate, 6:1;then silica gel, CH₂Cl₂/MeOH, 50:1) to afford trioxolane OZ331 (0.48 g,61%) as a colorless solid. mp 146-149° C.; ¹H NMR (500 MHz, CDCl₃) δ1.26-1.41 (m, 2H), 1.59-2.07 (m, 21H), 3.28 (d, J=6.3 Hz, 2H), 3.91 (s,3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.43, 26.82, 29.18, 33.29, 33.67,34.75, 35.81, 36.34, 36.74, 39.10, 108.27, 111.47, 154.42. Anal Calcdfor C₁₉H₂₈N₄O₃S: C, 58.14; H, 7.19; N, 14.27. Found: C, 58.15; H, 7.04;N, 14.50.

[0335]cis-Adamantane-2-spiro-3′-8′-[[(1′-methyl-1′H-tetrazol-5′-yl)sulfonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ332). To a solution of OZ331 (320 mg, 0.815 mmol) in CH₂Cl₂ (5 ml) at0° C. was added dropwise a solution of 3-chloroperoxybenzoic acid (70%reagent, 630 mg, 2.8 mmol) in CHCl₃/CH₂Cl₂ (1:1, 12 ml). After 2 h, themixture was allowed to warm up to rt, stirred at rt overnight, anddiluted with saturated aq. NaHCO₃ (25 ml). The mixture was stirred foran additional 1.5 h. The aqueous layer was extracted with CH₂Cl₂ (2×15ml). The combined organic solutions were washed with water and brine,dried over MgSO₄, filtered, and concentrated. The crude product wastriturated with 60% aq. ethanol and recrystallized from CH₂Cl₂/95% aq.ethanol (1:4) to afford trioxolane OZ332 (260 mg, 75%) as a colorlesssolid. mp 140-141° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.42-1.56 (m, 2H),1.64-2.09 (m, 20H), 2.16-2.28 (m, 1H), 3.63 (d, J=6.4 Hz, 2H), 4.36 (s,3H); ¹³C NMR (125.7 MHz, CDCl₃).26.42, 26.81, 29.86, 30.94, 33.55,34.75, 36.05, 36.34, 36.72, 60.88, 107.42, 111.70, 153.70. Anal Calcdfor C₁₉H₂₈N₄O₅S: C, 53.76; H, 6.65; N, 13.20. Found: C, 53.61; H, 6.46;N, 13.31.

[0336]cis-Adamantane-2-spiro-3′-8′-[[[(1′-aminocyclohexyl)carbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ333). To a solution of 1-amino-1-cyclohexanecarboxylic acid (172 mg,1.2 mmol), EDCI (290 mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF(10 ml) under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resulting mixturewas stirred at rt for 16 h, quenched with water (70 ml), and basifiedwith 1 M aq. NaOH (4 ml). The precipitate was collected by filtrationand recrystallized from 40% aq. ethanol to afford trioxolane OZ333 (330mg, 79%) as a colorless solid. mp 147-150° C.; ¹H NMR (500 MHz, CDCl₃) δ1.15-2.08 (m, 33H), 3.10 (app t, J=6.4 Hz, 2H), 7.93 (s, 1H); ¹³C NMR(125.7 MHz, CDCl₃) δ 21.24, 25.19, 26.46, 26.85, 27.73, 33.81, 34.67,34.77, 36.37, 36.40, 36.78, 44.24, 57.32, 108.70, 111.28, 177.94. AnalCalcd for C₂₄H₃₈N₂O₄: C, 68.87; H, 9.15; N, 6.69. Found: C, 68.94; H,9.07; N, 6.82.

[0337]cis-Adamantane-2-spiro-3′-8′-[(aminooxy)methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ334). Step 1. To a solution of OZ119 (294 mg, 1 mmol),triphenylphosphine (393 mg, 1.5 mmol), N-hydroxyphthalimide (245 mg, 1.5mmol) in THF (15 ml) at 0° C. was added dropwise diisopropylazodicarboxylate (364 mg, 1.8 mmol). After the stirring was continued atrt for 16 h, the mixture was concentrated. The residue was purified byflash chromatography (silica gel, 14% ethyl acetate in hexanes) toafford the desired phthalimide derivative (440 mg, 100%) as a colorlesssolid. mp 155-157° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.31-1.39 (m, 2H),1.68-2.00 (m, 21H), 4.02 (d, J=6.8 Hz, 2H), 7.73-7.76 (m, 2H), 7.82-7.84(m, 2H). Step 2. A mixture of above phthalimide derivative (400 mg, 0.91mmol) and hydrazine monohydrate (275 mg, 5.5 mmol) in chloroform/ethanol(7:3, 10 ml) was heated at 5560° C. for 24 h. After being cooled to rt,the solid by-product was filtered off. The filtrate was diluted withCHCl₃ (10 ml), washed with water (2×20 ml) and brine (20 ml), dried overMgSO₄, and concentrated. The residue was dissolved in ether (8 ml), andthen a solution of methanesulfonic acid (88 mg, 0.91 mmol) in CH₂Cl₂ (2ml) was added. The resulting mixture was diluted with ether (8 ml), andthe precipitate was collected by filtration to afford trioxolane OZ334(250 mg, 69%) as a colorless solid. mp 125-126° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.19-1.36 (m, 2H), 1.58-2.07 (m, 21H), 2.82 (s, 3H), 3.91 (d,J=5.8 Hz, 2H), 10.21 (s, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.43, 26.47,26.86, 33.44, 34.68, 34.77, 36.37, 36.79, 39.44, 79.49, 108.33, 111.42.Anal Calcd for C₁₈H₃₁NO₇S.0.13CH₂Cl₂: C, 52.31; H, 7.57; N, 3.37. Found:C, 52.57; H, 7.06; N, 3.42.

[0338]cis-Adamantane-2-spiro-3′-8′-[[[(2′S)-2′-aminopropionyl]amino]methyl]-30 1′,2′,4′-trioxaspiro[4.5]decane (OZ335). To a solution of Fmoc-Ala-OH(375 mg, 1.2 mmol), EDCI (290 mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol)in DMF (10 ml) under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol)and triethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The resultingmixture was stirred at rt for 16 h before being quenched with water (70ml). The precipitate was collected by filtration and dissolved in 10%piperidine in DMF (20 ml). The resulting mixture was stirred at rtovernight, diluted with water (70 ml), and extracted with CHCl₃ (3×30ml). The combined extracts were washed with water and brine, dried overMgSO₄, and concentrated. The residue was triturated with hexanes toafford trioxolane OZ335 (100 mg, 27%) as a colorless solid. mp 115-117°C.; ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.31 (m, 2H), 1.34 (d, J=6.8 Hz, 3H),1.41-2.05 (m, 23H), 3.12 (app t, J=6.4 Hz, 2H), 3.49 (q, J=7.0 Hz, 1H),7.39 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 21.91, 26.47, 26.86, 27.75,33.79, 34.78, 36.33, 36.38, 36.79, 44.16, 50.81, 108.66, 111.33, 175.60.Anal Calcd for C₂₀H₃₂N₂O₄: C, 65.91; H, 8.85; N, 7.69. Found: C, 66.08;H, 8.68; N, 7.59.

[0339]cis-Adamantane-2-spiro-3′-8′-[[(3′-aminopropionyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ336). To a solution of Fmoc-β-Ala-OH (375 mg, 1.2 mmol),EDCI (290 mg, 1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF (10 ml)under N₂ was added a solution of OZ209 (389 mg, 1.0 mmol) andtriethylamine (101 mg, 1.0 mmol) in DMF (5 ml). The mixture was stirredat rt for 16 h before being quenched with water (70 ml). The precipitatewas collected by filtration and dissolved in 10% piperidine in DMF (20ml). The resulting mixture was stirred at rt overnight, diluted withwater (70 ml), and extracted with CHCl₃ (3×30 ml). The combined extractswere washed with water and brine, dried over MgSO₄, and concentrated.The residue was triturated with CH₂Cl₂/hexanes (1:10, 11 ml), and thesolid was dissolved in CH₂Cl₂ (5 ml). After a solution ofp-toluenesulfonic acid monohydrate (127 mg, 0.67 mmol) in methanol (2ml) was added, the mixture was concentrated and triturated withCH₂Cl₂/ether (1:2, 15 ml) to afford trioxolane OZ336 (220 mg, 41%) as acolorless solid. mp 166° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 0.98-1.13(m, 2H), 1.33-1.95 (m, 21H), 2.28 (s, 3H), 2.43 (t, J=6.8 Hz, 2H), 2.93(app t, J=6.1 Hz, 2H), 2.94-3.02 (m, 2H), 7.11 (d, J=7.8 Hz, 2H), 7.47(d, J=8.3 Hz, 2H), 7.64 (s, 3H), 8.08 (t, J=5.7 Hz, 1H); ¹³C NMR (125.7MHz, DMSO-d₆) δ 20.95, 25.97, 26.38, 27.67, 32.00, 33.41, 34.42, 35.56,35.79, 35.92, 36.25, 43.90, 108.71, 110.66, 125.68, 128.23, 137.79,145.89, 169.53. Anal Calcd for C₂₇H₄₀N₂O₇S: C, 60.42; H, 7.51; N, 5.22.Found: C, 60.37; H, 7.31; N, 5.22.

[0340]cis-Adamantane-2-spiro-3′-8′-[[[(2′S)-2′-pyrrolidinylcarbonyl]amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ337). To a solution of Fmoc-Pro-OH (410 mg, 1.2 mmol), EDCI (290 mg,1.5 mmol), and HOBt (200 mg, 1.5 mmol) in DMF (10 ml) under N₂ was addeda solution of OZ209 (389 mg, 1.0 mmol) and triethylamine (101 mg, 1.0mmol) in DMF (5 ml). The mixture was stirred at rt for 16 h before beingquenched with water (70 ml). The precipitate was collected by filtrationand dissolved in 10% piperidine in DMF (20 ml). The resulting mixturewas stirred at rt overnight before being diluted with water (70 ml). Theprecipitate was collected by filtration and triturated twice withhexanes to afford trioxolane OZ337 (180 mg, 46%) as a colorless solid.mp 132-134° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.34 (m, 2H), 1.44-2.25(m, 25H), 2.81-2.96 (m, 1H), 2.97-3.06 (m, 1H), 3.10 (app t, J=6.3 Hz,2H), 3.66-3.80 (m, 1H), 7.72 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.20, 26.46, 26.85, 27.73, 30.78, 33.78, 33.79, 34.77, 36.36, 36.78,44.03, 47.28, 60.64, 108.66, 111.29, 175.11. Anal Calcd for C₂₂H₃₄N₂O₄:C, 67.66; H, 8.78; N, 7.17. Found: C, 67.71; H, 8.65; N, 7.19.

[0341]cis-Adamantane-2-spiro-3′-8′-[[[(3′S)-3′-amino-1′-pyrrolidinyl]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanemesylate (OZ338). Step 1. To a solution of the OZ78 active ester (880mg, 2 mmol) in CHCl₃ (40 ml) was added(3S)-3-(tert-butoxycarbonylamino)pyrrolidine (447 mg, 2.4 mmol). Theresulting mixture was stirred at rt for 1 h before being evaporated. Theresidue was crystallized from 50% aq. ethanol (40 ml) to give the amideintermediate (577 mg, 59%, 2:1 mixture of rotamers). mp 97-100° C.; ¹HNMR (500 MHz, CDCl₃) δ 1.16-1.32 (m, 2H), 1.45 (s, 9H), 1.60-2.06 (m,22H), 2.09-2.27 (m, 3H), 3.21-3.41 (m, 1H), 3.43-3.62 (m, 2H), 3.64-3.79(m, 1H), 4.09-4.28 (m, 1H), 4.49-4.73 (m, 1H); ¹³C NMR (125.7 MHz,CDCl₃) δ 26.48, 26.85, 28.34, 30.18, 30.23, 30.26, 32.38, 32.95, 33.00,34.04, 34.05, 34.78, 36.38, 36.79, 40.65, 41.05, 43.56, 44.74, 52.71,108.63, 108.65, 111.28, 111.32, 155.15, 170.97. Step 2. To a solution ofthe above amide (491 mg, 1.0 mmol) in ether (30 ml) was added a solutionof methanesulfonic acid (481 mg, 5.0 mmol) in ether (20 ml). Theresulting mixture was stirred at rt for 48 h. After the solvent wasdecanted off, the residue was washed with ether (20 ml) and crystallizedfrom EtOAc/EtOH (3:1, 20 ml) to give trioxolane OZ338 (231 mg, 47%, 2:1mixture of rotamers) as a colorless solid. mp 146° C. dec; ¹H NMR (500MHz, CDCl₃) δ 1.11-1.34 (m, 2H), 1.45-2.05 (m, 21H), 2.06-2.27 (m, 3H),2.28-2.41 (m, 1H), 2.74 (s, 3H), 3.43-4.01 (m, 5H), 7.96 (s, 2H), 8.02(s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) 826.48, 26.87, 28.55, 30.11, 30.14,30.18, 30.24, 30.31, 32.81, 32.86, 34.02, 34.08, 34.79, 36.39, 36.79,39.39, 40.74, 40.99, 43.32, 44.32, 49.34, 49.38, 50.20, 50.94, 108.49,108.60, 111.30, 111.35, 171.20, 171.83. Anal Calcd for C₂₃H₃₈N₂O₇S: C,56.77; H, 7.87; N, 5.76. Pound: C, 56.91; H, 7.66; N, 5.67.

[0342]cis-Adamantane-2-spiro-3′-8′-[[(4′-amino-1′-piperidinyl)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate (OZ339). Step 1. To a solution of the OZ78 active ester (880mg, 2 mmol) in CHCl₃ (40 ml) was added4-(tert-butoxycarbonylamino)piperidine (481 mg, 2.4 mmol). The resultingmixture was stirred at rt for 1 h before being evaporated. The residuewas crystallized from 50% aq. ethanol (80 ml) to give the amideintermediate (995 mg, 99%). mp 146-148° C.; ¹H NMR (500 MHz, DMSO-d₆) δ1.02-1.29 (m, 4H), 1.38 (s, 9H), 1.59-1.94 (m, 23H), 2.19 (d, J=6.8 Hz,2H), 2.63 (dd, J=11.8, 11.8 Hz, 1H), 3.02 (dd, J=12.2, 12.2 Hz, 1H),3.39-3.51 (m, 1H), 3.80 (d, J=13.7 Hz, 1H), 4.23 (d, J=13.2 Hz, 1H),6.84 (d, J=7.8 Hz, 1H). Step 2. A mixture of the above amide (505 mg, 1mmol) and p-toluenesulfonic acid monohydrate (951 mg, 5 mmol) inEtOAc/isopropanol (9:1, 50 ml) was stirred at rt for 48 h. Theprecipitate was filtered, washed with EtOAc (20 ml), dissolved in 20%aq. ethanol (90 ml), and basified with 14% aq. KOH (10 ml). The solidwas filtered, dissolved in CHCl₃, dried over MgSO₄, and concentrated. Toa solution of the above free base (170 mg) in EtOAc (10 ml) was added asolution of p-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol) inEtOAc (10 ml). The precipitate was collected by filtration, washed withEtOAc (10 ml), and dried to give trioxolane OZ339 (180 mg, 31%) as acolorless solid. mp 154-156° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 1.05-1.18(m, 2H), 1.20-1.29 (m, 1H), 1.30-1.42 (m, 1H), 1.59-1.97 (m, 23H), 2.22(d, J=5.4 Hz, 2H), 2.29 (s, 3H), 2.57 (dd, J=11.8, 11.8 Hz, 1H), 3.02(dd, J=12.2, 12.2 Hz, 1H), 3.24 (br s, 1H), 3.92 (d, J=13.7 Hz, 1H),4.39 (d, J=13.2 Hz, 1H), 7.12 (d, J=7.8 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H),7.82 (s, 3H); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 20.94, 25.97, 26.37, 29.61,29.77, 30.48, 32.73, 33.67, 34.41, 35.93, 36.25, 38.37, 43.32, 47.66,47.75, 108.58, 110.62, 125.64, 128.23, 137.81, 145.84, 169.78. AnalCalcd for C₃₀H₄₄N₂O₇S: C, 62.47; H, 7.69; N, 4.86. Found: C, 62.57; H,7.54; N, 4.76.

[0343]cis-Adamantane-2-spiro-3′-8′-(2′-oxo-2′-hydrazinoethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ340). To a stirred solution of the methyl ester of OZ78 (0.68 g, 2mmol) in methanol (10 ml) and THF (5 ml) was added hydrazine monohydrate(3 ml, 60 mmol). The resulting mixture was heated at 50-60° C. for 24 h,then cooled to rt, and concentrated. The residue was dissolved in EtOAc(100 ml), washed with water (50 ml) and brine (50 ml), dried over MgSO₄,and filtered. After removal of the solvent, the crude product waspurified by crystallization from CH₂Cl₂/EtOH to afford trioxolane OZ340(0.56 g, 83%) as a colorless solid. mp 124-126° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.15-1.35 (m, 2H), 1.61-2.02 (m, 21H), 2.03 (d, J=6.8 Hz, 2H),3.55-4.09 (m, 2H), 6.76 (s, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.46,26.85, 29.99, 33.36, 33.91, 34.77, 36.37, 36.77, 41.23, 108.43, 111.40,172.77. Anal Calcd for C₁₈H₂₈N₂O₄: C, 64.26; H, 8.39; N, 8.33. Found: C,64.12; H, 8.42; N, 8.12.

[0344]cis-Adamantane-2-spiro-3′-8′-(2′-oxo-2′-guanidinoethyl)-1′,2′,4′-trioxaspiro[4.5]decane(OZ341). A solution of potassium tert-butoxide (0.56 g, 5.0 mmol) andguanidine hydrochloride (0.48 g, 5.0 mmol) in dioxane (20 ml) was heatedunder N₂ at 50° C. for 20 min. After the mixture was cooled to rt, asolution of the OZ78 active ester (0.46 g, 1.05 mmol) in CHCl₃ (20 ml)was added dropwise. The mixture was stirred at rt for 4 h and thenconcentrated. After addition of water (30 ml), the resulting precipitatewas collected, washed with water, and dried to give trioxolane OZ341(0.36 g, 94%) as a colorless solid. mp 146-147° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.19-1.35 (m, 2H), 1.61-2.07 (m, 21H), 2.21 (d, J=7.3 Hz, 2H);¹³C NMR (125.7 MHz, CDCl₃) δ 26.49, 26.89, 30.13, 33.71, 34.16, 34.80,36.39, 36.82, 47.35, 108.87, 111.21, 161.10. Anal Calcd for C₁₉H₂₉N₃O₄:C, 62.79; H, 8.04; N, 11.56. Found: C, 63.00; H, 7.88; N, 11.42.

[0345]cis-Adamantane-2-spiro-3′-8′-[[(1′,1′-dioxido-4′-thiomorpholinyl)carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane(OZ342). Step 1. To a solution of the OZ78 active ester (0.5 g, 1.14mmol) in CHCl₃ (15 ml) was added dropwise a solution of thiomorpholine(0.15 g, 1.45 mmol) in CHCl₃ (10 ml). The resulting mixture was stirredat rt for 1.5 h and then quenched with water (30 ml). After separationof the organic layer, the aqueous layer was extracted with CHCl₃ (2×20ml). The combined extracts were washed with water (2×20 ml) and brine(20 ml), dried over MgSO₄, and filtered. After removal of the solvent,the crude product was purified by crystallization from ether to affordthe thioether intermediate (0.45 g, 97%) as a colorless solid. mp126-127° C.; ¹H NMR (500 MHz, CDCl₃) δ 1.15-1.31 (m, 2H), 1.59-2.05 (m,21H), 2.20 (d, J=6.8 Hz, 2H), 2.57-2.63 (m, 4H), 3.69-3.78 (m, 2H),3.85-3.92 (m, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ 26.48, 26.86, 27.46,27.94, 30.31, 33.21, 34.05, 34.79, 36.39, 36.79, 39.36, 44.29, 48.41,108.59, 111.35, 170.40. Step 2. To a solution of the above thioetherintermediate (0.39 g, 0.96 mmol) in CH₂Cl₂ (10 ml) at 0° C. was addeddropwise a solution of m-CPBA (0.52 g, 2.1 mmol) in CH₂Cl₂ (15 ml). Theresulting mixture was stirred at rt for 24 h and then partitionedbetween CH₂Cl₂ (20 ml) and saturated aq. NaHCO₃ (20 ml). The organiclayer was washed with water (20 ml) and brine (20 ml), dried over MgSO₄,and filtered. After removal of the solvent, the crude product waspurified by crystallization from CH₂Cl₂/EtOH to afford trioxolane OZ342(0.34 g, 81%) as a colorless solid. mp 159-160° C.; ¹H NMR (500 MHz,CDCl₃) δ 1.15-1.33 (m, 2H), 1.59-2.03 (m, 21H), 2.26 (d, J=6.8 Hz, 2H),3.02 (s, 4H), 3.96 (s, 2H), 4.11 (s, 2H); ¹³C NMR (125.7 MHz, CDCl₃) δ26.46, 26.85, 30.25, 33.07, 33.96, 34.78, 36.38, 36.77, 39.04, 40.22,43.90, 52.14, 52.28, 108.35, 111.48, 170.54. Anal Calcd for C₂₂H₃₃NO₆S:C, 60.11; H, 7.57; N, 3.19. Found: C, 60.30; H, 7.43; N, 3.23.

EXAMPLE 2

[0346] Antimalarial Activity of OZ01-OZ342

[0347] Each trioxolane was screened against the chloroquine-resistant K1and chloroquine-sensitive NF54 strains of P. falciparum in vitro. In thesingle dose STI in vivo screen, Moro SPF or NMRI mice infected with theANKA strain of P. berghei (groups of three mice) were treated on day onepost-infection with trioxolanes dissolved or suspended in 3% ethanol and7% Tween 80. Trioxolanes were administered as single 10 mg/kg doses scand po. Trioxolanes were also administered as single 10 mg/kg doses instandard suspending vehicle (SSV). SSV consists of 0.5% w/v CMC, 0.5%v/v benzyl alcohol, 0.4% v/v Tween 80, and 0.9% w/v sodium chloride inwater. Antimalarial activity was measured by percent reduction inparasitemia on day three post-infection and survival times compared toan untreated control group. Survival to day 30 post-infection isconsidered to be a cure. In U.S. Pat. No. 6,486,199, Table 1 presenteddata for trioxolanes OZ01-OZ90 along with the controls, fenozan,artemisinin, arteether, artemether, and artesunate. The data showed thatantimalarial activity falls off both when the trioxolane peroxide bondis too exposed or is sterically inaccessible to iron(II) species. Otherfactors influencing antimalarial activity include the stability ofcarbon radicals formed by β-scission subsequent to the initial electrontransfer to the peroxide bond and the influence of steric effects remotefrom the peroxide bond on the interactions between carbon radicals andpotential drug targets. The data also demonstrated that trioxolanecarboxylic acids are usually less active than their hydrocarbon, ester,and hydroxamic acid counterparts.

[0348] Below is the activity data for OZ91-OZ342: TABLE 1 Activity (%)Survival (days) IC₅₀ (ng/ml) 10 mg/kg 10 mg/kg Compd K1/NF54 po/SSVpo/sc po/SSV po/sc NONE — 0 6-7 OZ91  1.4/0.42 20/0/85 5.7/6.0/7.3 OZ92 1.6/0.40 81/35/99.98 6.7/6.3/10.0 OZ93  3.3/0.92 57/3/100 6.7/6.0/13.3OZ94 57/28 21/0/11 6.0/5.7/5.3 OZ95 2.8/1.3 31/0/49 6.0/6.0/6.0 OZ96 8.4/>10 12/14/19 5.7/5.7/5.3 OZ97 2.2/1.8 59/2/66 6.7/5.3/7.0 OZ982.3/0.9 72/11/77 6.3/5.3/7.3 OZ99 77/27 30/40/36 6.3/5.7/6.3 OZ100 1.4/0.34 61/36/80 6.7/6.3/7.0 OZ101 3.0/1.6 44/0/99.97 6.3/5.3/13 OZ102 1.6/0.45 92/73/99.97 7.0/6.7/19.7 OZ103 0.64/0.17 86/63/87 7.3/6.7/7.3OZ104  1.4/0.50 56/0/99.98 6.3/5.7/12.0 OZ105 5.4/5.0 16/0/285.7/5.7/6.3 OZ106 2.2/1.7 0/0/0 5.3/5.05.3 OZ107  1.0/0.30 70/32/99.746.3/6.3/8.0 OZ108 68/29 0/0/0 5.0/5.0/5.7 OZ109 21/24 2/0/24 5.7/5.7/6.3OZ110 5.3/2.1 50/0/97.97 6.7/5.3/7.7 OZ111 0.92/0.35 98/79/99.947.7/6.3/8.3 OZ112 >10/>10 6/0/36 5.7/5.7/6.3 OZ113 0.95/0.20 92/96/897.3/8.0/7.3 OZ114 3.7/2.2 0/0/99.64 5.7/6.0/8.7 OZ115  11/6.9 33/0/976.3/5.7/7.3 OZ116 4.2/3.3 97/96/96 7.7/8.3/8.0 OZ117 2.1/1.2 95/96/99.947.0/7.7/8.7 OZ118  1.0/0.24 99.0/98/99.57 7.0/8.0/8.3 OZ119 0.83/0.2099.29/99.15/99.66 7.7/8.0/8.3 OZ120  1.2/0.59 33/8/96 6.0/5.7/8.0 OZ1210.96/0.41 91/98/99.61 7.3/8.0/7.3 OZ122 >100/>100 10/3/0 5.7/5.3/5.0OZ123 1.6/1.9 99.66/94/99.96 8.0/7.0/16 OZ124 2.1/1.7 72/17/866.3/5.3/7.0 OZ125    68/>100 8/0/0 5.3/5.7/6.0 OZ126 0.20/0.5055/72/99.44 7.0/6.7/8.5 OZ127 0.61/1.3  95/98/97 7.0/7.7/7.7 OZ1280.59/1.1  99.93/99.95/99.98 8.3/8.7/11.7 OZ129   10/>10 0/4/05.3/5.7/5.7 OZ130 0.62/0.94 98.8/98.9/98.6 9.0/8.0/7.3 OZ131 1.7/4.121/41/90 5.7/6.0/8.0 OZ132  9.8/>10 38/0/40 6.3/5.7/6.3 OZ133 0.70/1.1 94/97/72 7.0/7.3/7.0 OZ134 0.88/1.1  72/27/99.95 6.3/6.0/15.3OZ135 >100/>100 1/0/0 5.3/5.3/5.3 OZ136 23/21 0/0/0 6.0/6.0/6.0 OZ13711/18 0/6/61 5.7/6.3/7.0 OZ138 10/19 0/5/7 5.7/6.3/6.3 OZ140 5.9/8.20/8/60 6.0/6.3/7.0 OZ141 1.7/1.9 98/97/99.89 8.0/8.0/8.7 OZ142 2.3/2.30/2/99.98 6.0/6.3/14.3 OZ143 0.98/1.8  48/44/99.85 6.7/6.7/9.7 OZ1441.4/2.1 99.45/92/99.94 7.3/7.3/16.7 OZ145 0.50/0.76 99.82/99.21/99.878.3/10.7/10.7 OZ146 2.2/2.7 62/40/91 7.0/6.3/9.0 OZ147 1.1/1.885/71/99.89 8.0/8.0/19.7 OZ148 17/16 38/58/21 7.3/7.7/6.3 OZ149 8.0/8.864/3/87 7.7/6.0/14.3 OZ151 3.8/4.0 71/71/99.63 7.3/7.3/11.0 OZ1523.2/7.2 0/12/22 6.3/6.7/6.7 OZ153 7.7/19  15/23/20 6.3/7.0/6.3 OZ1545.0/6.1 99.74/81/59 14.7/8.7/7.7 OZ155   12/>10 53/53/73 6.3/7.0/8.3OZ156 2.1/2.1 99.98/98.8/99.98 17.0/10.3/19.7 OZ157 0.20/0.22 90/80/977.3/8.3/8.3 OZ159 0.70/0.94 34/31/98 6.7/6.7/9.0 OZ160 0.70/0.8745/43/99.94 6.3/6.7/12.0 OZ161 0.40/0.50 59/46/99.96 7.0/6.7/12.7 OZ1620.50/0.71 41/22/99.55 6.3/6.3/9.3 OZ163 0.2/0.2 99.90/99.94/1008.0/9.0/9.7 OZ164    9/>10 11/0/7 5.7/5.7/6.3 OZ165   39/>10 18/3/96.3/6.0/5.7 OZ166   28/>10 11/0/4 6.7/6.3/5.7 OZ167  6.7/>10 0/6/976.0/6.0/7.3 OZ169   15/>10 98/22/99.76 7.7/6.7/9.0 OZ171 1.3/1.498/85/99.94 9.0/7.0/9.7 OZ172 3.5/5.0 68/82/100 8.0/10.3/10.3 OZ17358/32 15/0/80 7.0/6.7/9.7 OZ174 27/34 0/15/90 6.7/7.3/10.3 OZ175 1.4/2.099.1/97/92 10.0/12.3/8.7 OZ176 25/35 11/18/24 7.0/7.7/7.0 OZ177 0.9/1.799.91/99.88/99.91 12.3/12.7/17.7 OZ178 21/27 32/23/31 7.3/7.3/10.0 OZ1791.3/1.1 99.91/99.78/99.91 11.3/10.3/11.3 OZ180 3.7/2.8 99.91/97/6513.7/12.7/10.3 OZ181 0.58/0.35 99.98/99.91/100 9.0/10.0/11.0 OZ1824.5/5.5 91/96/95 8.0/7.3/7.7 OZ183 0.80/2.1  65/19/81 6.0/6.0/8.3 OZ1841.0/1.4 54/59/97 6.7/7.0/8.7 OZ185 1.1/1.4 86/56/99.96 7.7/6.7/10.7OZ186 >10/>10 87/96/67 8.0/9.0/8.0 OZ187 4.0/6.8 77/94/77 7.7/10.0/7.0OZ188 1.5/3.0 93/98/99.87 8.7/10.0/9.0 OZ189 1.7/3.0 95/99.79/989.3/9.0/10.7 OZ190 0.16/1.0  98/78/2 8.7/7.7/5.7 OZ191  6.0/>10 7/5/175.7/5.7/6.0 OZ192 2.5/4.4 38/45/99.98 6.0/7.0/13.7 OZ193 5.5/8.399.75/93/99.92 9.3/8.0/11.0 OZ194 2.0/6.6 87/73/99.95 8.3/8.0/20.3 OZ1952.2/3.7 98/99.02/99.75 9.3/10.7/9.0 OZ196 >10/>10 10/0/17 6.0/5.3/5.7OZ197 1.0/2.0 87/90/99.54 7.7/8.7/10.3 OZ198 >10/>10 4/6/6 5.7/6.0/5.7OZ199 0.69/1.1  99.48/76/99.44 8.3/7.7/8.7 OZ200 1.0/2.9 81/78/927.0/7.3/8.0 OZ201 2.0/3.1 100/100/100 13/10.3/25 OZ202 6.0/7.9 79/51/747.0/7.3/7.3 OZ203 3.9/6.7 87/99.42/99.72 7.3/8.7/9.7 OZ204 >10/>10 0/0/06.0/6.3/6.0 OZ205 1.5/2.0 99.96/99.94/99.96 10.0/8.7/9.7 OZ206 1.0/2.793/92/91 8.0/8.7/9.7 OZ207 0.33/0.57 99.96/99.98/99.98 9.3/12.0/11.3OZ208 6.0/6.5 0/29/10 6.3/6.7/5.7 OZ209 0.21/0.32 99.94/99.96/99.979.5/10.0/12.5 OZ210 1.4/1.6 99.23/77/99.94 9.3/8.0/10.3 OZ211 1.0/1.282/78/99.90 8.0/7.3/8.7 OZ212 2.7/2.9 66/25/59 6.7/6.7/8.0 OZ213 2.3/2.883/74/85 8.0/8.0/8.0 OZ214 >10/>10 44/54/65 6.3/7.3/7.7 OZ215 6.4/7.396/25/39 9.76.3/7.0 OZ216 0.40/0.67 62/69/99.02 6.3/7.7/11.0 OZ2172.0/2.0 67/8/98 7.0/6.0/8.0 OZ218 2.0/3.0 98/99.30/99.68 10.0/14.3/9.0OZ219 0.85/1.6  99.89/99.82/99.91 8.7/8.0/9.3 OZ220 6.9/4.9 40/0/99.956.0/5.3/10.0 OZ221 >10/>10 80/87/97 6.3/7.0/8.0 OZ222 3.9/6.387/75/99.76 7.7/7.0/10.0 OZ223  4.0/>10 89/79/99.57 7.3/6.3/12.0 OZ2242.0/3.0 0/5/20 6.0/5.7/5.7 OZ225  7.3/>10 0/0/17 5.7/5.7/6.3 OZ2264.0/4.0 0/0/99.92 5.0/5.3/11.0 OZ227 0.20/0.20 99.68/99.90/99.848.3/9.3/10.7 OZ228 2.0/2.1 99.94/28/99.94 10.3/6.0/14.0 OZ229 0.24/0.2399.96/99.08/99.98 10.0/8.3/12.7 OZ230 3.9/3.6 0/0/0 5.3/5.7/5.7OZ231 >10/>10 0/0/0 5.3/5.7/6.0 OZ232 0.30/0.50 76/74/99.94 8.0/7.3/8.7OZ233 1.7/1.9 69/76/99.66 7.0/7.7/8.3 OZ234 3.0/3.6 12/0/0 6.0/6.0/6.3OZ235 1.0/2.0 99.92/99.97/97 8.7/9.0/8.0 OZ236 2.0/2.0 89/86/98.616.3/7.7/7.7 OZ237 5.7/7.1 5/9/52 6.0/6.0/6.7 OZ243 0.91/1.1  87/97/707.3/8.7/6.3 OZ244 4.0/4.2 6/0/18 5.7/5.3/6.3 OZ247 1.8/2.3 57/27/99.856.3/6.0/9.0 OZ251 0.60/0.35 29/6/99.87 6.7/6.0/9.0 OZ252 2.3/2.298.91/99.49/99.82 8.3/9.0/9.3 OZ253 0.56/0.45 75/59/99.82 7.0/6.7/9.3OZ254 >100/57    27/11/2 6.0/5.7/5.7 OZ255 2.2/1.1 99.61/99.54/99.929.0/8.7/10.0 OZ256 0.3/0.2 99.70/99.67/99.95 8.7/8.7/9.7 OZ257 42/2199.00/99.49/99.84 8.3/7.7/9.7 OZ258 5.8/5.2 75/70/99.95 6.0/6.0/10.7OZ260 5.6/4.3 72/51/81 6.7/7.0/7.7 OZ261 39/18 61/47/92 7.0/7.0/8.0OZ262 0.63/0.84 96/98/99.39 11.7/12.3/10.0 OZ263 0.84/1.1 99.53/99.45/99.92 13.0/13.3/11.0 OZ264 1.2/1.5 99.61/99.92/99.9711.0/10.3/13.7 OZ265 0.56/1.6  99/98/99.67 13.0/9.7/11.7 OZ266 1.1/1.599/99.39/99.75 13.7/11.7/11.7 OZ267 0.20/0.34 99.92/99.89/99.978.3/8.7/9.3 OZ268 0.44/0.71 99.86/99.47/99.92 9.3/13.3/9.7 OZ2690.32/0.61 98/86/99.92 10.7/11.3/9.0 OZ270 0.85/1.3  99.17/99.47/99.8113.7/12.3/11.3 OZ271 0.36/0.29 99.93/99.52 8.7/8.6 OZ272 1.1/1.3 98/4910.3/6.6 OZ273 0.97/1.0  99.58/64 11.7/7.2 OZ274 5.1/5.7 11/ND 7.0/NDOZ275 0.66/0.74 68/ND 7.3/ND OZ276 0.86/0.94 17/ND 7.3/ND OZ2770.57/0.58 99.98/99.28 9.3/9.6 OZ278 23/39 56/ND 7.3/ND OZ279 0.21/0.2499.98/99.42 9.3/8.4 OZ280 1.2/1.4 0/ND 5.7ND OZ281 0.50/0.30 99.87/968.7/10.2 OZ282 2.0/2.4 98.5/53 8.3/7.2 OZ283 1.7/2.0 99.81/56 8.3/8.2OZ284 1.0/1.4 97/61 9.0/7.8 OZ285 1.3/1.8 99.81/72 8.7/7.6 OZ2860.94/1.6  99.73/60 8.7/7.0 OZ287 0.49/0.83 95/68 8.3/7.2 OZ288 1.7/2.799.96/82 11.0/8.0 OZ289 0.40/0.56 99.94/92 13.4/7.4 OZ290 0.42/0.4599.64/95 9.0/7.0 OZ291 0.52/0.72 98/34 8.0/6.8 OZ292 0.19/0.26 74/467.0/6.6 OZ293 0.25/0.34 99.58/77 8.8/7.4 OZ294 0.39/0.63 99.79/708.6/7.4 OZ295 0.44/0.75 47/35 7.0/6.4 OZ296 0.60/0.89 99.22/90 10.0/9.2OZ297 0.49/0.76 99.69/83 9.8/7.6 OZ298 2.0/3.0 99.95/98 9.4/9.0 OZ2996.8/6.3 36/0 6.6/6.4 OZ300 71/97 6/0 6.8/7.0 OZ301 2.1/2.8 100/9711.8/8.4 OZ302 1.9/2.9 99.60/88 9.0/9.0 OZ303 1.6/2.4 99.01/69 8.6/7.6OZ304 1.6/2.3 98/61 8.2/8.8 OZ305 1.8/1.9 99.93/96 9.2/9.6 OZ306 3.9/3.699.58/87 9.2/8.2 OZ307 0.62/0.88 98/74 9.4/7.8 OZ308 1.2/1.7 86/307.8/6.6 OZ309 11/17 99.80/86 8.8/7.8 OZ310 0.82/1.1  81/38 7.8/8.2 OZ3111.2/1.8 80/40 8.6/7.0 OZ312 19/27 43/13 7.2/6.2 OZ313 0.55/0.76 98.9/5810.4/7.4 OZ314 11/17 13/11 6.6/6.6 OZ315 2.8/3.0 99.97/92 11.2/9.6 OZ3161.0/1.7 69/7 10.0/8.0 OZ317 0.33/0.36 99.92/99.20 9.8/10.0 OZ3180.56/0.82 88/29 12.4/7.6 OZ319 0.41/0.91 99.92/99.14 10.6/10.8 OZ3200.68/1.30 99.76/92 10.4/11.8 OZ321 0.58/0.97 99.77/64 14.0/9.8 OZ3220.90/1.5  98/61 10.0/9.4 OZ323 0.85/1.1  99.98/99.92 15.6/9.2 OZ3242.4/3.4 60/26 9.4/7.4 OZ325 0.62/1.4  99.43/30 8.8/6.2 OZ326 0.65/1.2 80/7 7.4/6.0 OZ327 0.85/1.1  97/72 9.8/7.0 OZ328 1.4/3.0 99.77/758.6/7.6 OZ329 0.43/0.68 99.97/99.50 11.2/9.2 OZ330 0.55/1.2  99.96/8212.2/7.2 OZ331 0.50/1.2  99.47/66 9.0/7.0 OZ332 1.7/2.5 8/0 6.0/6.0OZ333 0.24/0.44 99.86/96 9.2/8.0 OZ334 28/20 47/13 6.8/6.6 OZ3350.29/0.28 99.95/97 9.2/10.0 OZ336  1.4/0.91 99.93/98 9.2/9.6 OZ3370.29/0.25 99.92/97 8.6/11.6 OZ338 0.38/0.45 99.93/99.80 9.8/8.0 OZ3390.35/0.39 99.95/99.65 10.2/9.2 OZ340 4.9/2.9 93/36 9.2/6.4 OZ341 2.4/2.097/32 8.0/7.0 OZ342 1.8/1.2 27/0 6.8/6.4 AM 0.45/0.36 99.75/79 9.4/8.7AS 1.4/1.5 87/66 7.0/8.0 CQ  76/4.4 99.92/82 9.0/8.0 MFQ 2.2/5.0 99.11/917/6.3

[0349] As shown in the inventors' earlier studies with OZ01 to OZ90,antimalarial activity falls off when the trioxolane peroxide bond is tooexposed or is sterically inaccessible to iron(II) species. Other factorsinfluencing antimalarial activity include the stability of carbonradicals formed by β-scission subsequent to the initial electrontransfer to the peroxide bond and the influence of steric effects remotefrom the peroxide bond on the interactions between carbon radicals andpotential drug targets. The new activity data demonstrates thattrioxolane carboxylic acids are usually less active than theirhydrocarbon, ester, amide, and hydroxamic acid counterparts. Theposition of ionizable functional groups such as carboxylic acids andamines is also critical to activity. The best combination of highintrinsic potency and good oral activity is found when a weak basefunctional group is present.

EXAMPLE 3 Onset of Action and Recrudescence of OZ11, OZ27, OZ78, OZ156,OZ175, OZ177, OZ207, OZ209, OZ277, and OZ279

[0350] Onset of Action and Recrudescence Experiments

[0351] The onset of drug action was determined after a single fixed doseof 100 mg/kg (SSV vehicle) po to groups of five animals on day +3post-infection (day 0). Parasitemias at this point are usually between25-40%. The infected controls do not survive beyond day +6post-infection. The reduction of parasitemia is monitored 12, 24, and 48h after treatment, and the time of recrudescence (>5% parasitemia) isassessed by daily blood smears for 14 days, followed by intermittentassessment for up to 60 days.

[0352] The onset part of this experiment reveals how rapidly a compoundreduces parasite load; the recrudescence part of the experiment providesinformation about the efficacy of the compound against the parasite. Along delay in recrudescence can be due to a very good antiparasiticeffect of the compound or to a compound with a long half-life.

[0353] Both the trioxolanes and the artemisinins produced a rapiddecline in parasitemia, confirming that they are rapidly actingantimalarial agents. In contrast to both chloroquine and these peroxidicantimalarials, mefloquine has a slow onset of action. Recrudescence (>5%parasitemia) occurs quite rapidly for artemisinin and artesunate. Thetime of recrudescence increased for the more lipophilic artemisininderivatives artemether and arteether.

[0354] In contrast to artemether, recrudescence occured much more slowlyfor the lipophilic trioxolanes OZ11 and OZ27; the recrudescence time forOZ27 was especially marked, superior to that of mefloquine. However,recrudescence times for the relatively polar trioxolanes OZ78, OZ175,and OZ277 were very similar to that of artemether. The more lipophilictrioxolane (OZ156) of the OZ156/OZ177 pair produced the longest delay inrecrudescence, longer than chloroquine, but less than mefloquine. Therecrudescence times for OZ177 and OZ279 were roughly equivalent to thatof chloroquine.

[0355] Strikingly, there was no recrudescence observed for OZ207 andOZ209, two different salt forms (OZ207—tosylate, OZ209—mesylate) ofaminomethyl trioxolane OZ163 (hydrochloride). The recrudescence data forthese two trioxolanes suggests that they are either more powerfulantimalarial agents or have longer half-lives than any of thesemisynthetic artemisinins. TABLE 2 Compd Time of Recrudescence (days)OZ11 22.2 OZ27 22.0 (3/5), >60 (2/5) OZ78 11.2 OZ156 19.0 (4/5), >60(1/5) OZ175 13.0 OZ177 18.5 OZ207 >60 OZ209 >60 OZ277 13.0 OZ279 15.0Artemisinin 8.4 Artesunate 8.6 Artemether 12.0 Arteether 11.4Chloroquine 17.8 Mefloquine 28.0

EXAMPLE 4 Effect of Trioxolanes on Schistosoma Species

[0356] Effect of Trioxolane OZ207 on Schistosoma japonicum TABLE 3Comparative effect of OZ207 and artemether in mice infected withSchistosoma japonicum Mice Age of Dose without MTWB/ MFWB/ FWR Drug worm(mg/kg × 1) ♀ worm x ± SD WRR/% x ± SD R/% Control — — 0/8 26.6 ± 4.2  —11.6 ± 2.4  — OZ207 35 200 4/7 9.1 ± 3.9 66 0.6 ± 0.7 95 days OZ207 35400 4/6 4.3 ± 1.2 84 0.7 ± 1.2 94 days Artemether 35 400 0/7 10.1 ± 4.4 62 3.4 ± 1.6 71 days OZ207  7 200 0/8 5.4 ± 2.4 81 2.1 ± 1.0 82 days

[0357] Table 3 illustrates that the mean total worm burden and meanfemale worm burden in OZ207 400 mg/kg group was significantly lower thanthose in artemether 400 mg/kg group (P<0.01). The mean female wormburden in OZ207 200 mg/kg group was also significantly lower than thatin artemether group (P<0.01).

[0358] Effect of Trioxolanes on 21-Day-Old Schistosomules

[0359] Mice were infected with 100 Schistosoma mansoni cercariae on day21 post-treatment. Each group was treated per os with trioxolanes at asingle dose of 200 mg/kg. Untreated mice served as the control. Allgroups were killed 4 weeks after treatment and the liver and intestinewere removed and separated. The liver and intestine were compressed andalive male and female worms could be seen and counted. The effect of thecompounds was evaluated by mean total and female worm burden. Theresults are shown in Table 5.

[0360] Effect of Trioxolanes on Adult Schistosomes (49-Day-Old)

[0361] Mice were infected with 100 Schistosoma mansoni cercariae on day49 post-treatment. Each group was treated per os with OZ compounds atsingle doses of 200, 400, and 600 mg/kg. Untreated mice served as thecontrol. All groups were killed 4 weeks after treatment and the liverand intestine were removed and separated. The liver and intestine werecompressed and alive male and female worms could be seen and counted.The effect of the compounds was evaluated by mean total and female wormburden, and the results are set forth in Table 4. TABLE 4 IN VIVOACTIVITY AGAINST SCHISTOSOMA MANSONI (MICE INFECTED) % reduction ofadult worms growth % reduction of at day 49 after per os schistosomulegrowth application of . . . mg/kg at day 21 after per os 200 OZapplication TWR (%)/ COMPOUNDS of 200 mg/kg DEAD TESTED TWR (%) FWR (%)WORM (%) 400 600 OZ 03 liquid 74 74 29/8  OZ 04 7 7 0/0 OZ 05 90 8846/12  23/32* 70/58 OZ 10 66 73 28/13 21/23 OZ 11 85 84 16/4  OZ 12 7879 14/0  OZ 14 7 0 0/0 OZ 15 63 70  0/10 OZ 16 78 77 ND OZ 17 23 7 0/5OZ 18 12 9 0/0 OZ 19 77 74 ND OZ 20 0 0 0/0 OZ 21 0 0 0/0 OZ 22 liquid75 76 ND OZ 23 90 84 0/4 OZ 24 65 61 21/0  OZ 25 86 84 46/34 OZ 26 37 40ND OZ 27 63 58 20/10 OZ 28 81 87 ND OZ 29 28 20 0/0 OZ 30 16 12 ND OZ 3160 63 4/4 OZ 32 73 70 27/28 OZ 33 28 14 ND OZ 35 73 63 ND OZ 36 16 120/0

[0362] IN VIVO ACTIVITY AGAINST SCHISTOSOMA MANSONI (MICE INFECTED) %reduction of adult worms growth % reduction of at day 49 after per osschistosomule growth application of . . . mg/kg at day 21 after per os200 OZ application TWR (%)/ COMPOUNDS of 200 mg/kg DEAD TESTED TWR (%)FWR (%) WORM (%) 400 600 OZ 37 63 53 ND OZ 43 ND ND 1/0 OZ 49 ND ND17/10 OZ 50 ND ND 12/4  OZ 56 69 66 ND OZ 61 ND ND  8/21 OZ 67 ND ND38/0  OZ 68 ND ND 17/0* OZ 71 91 85  0/16 OZ 72 ND ND  0/10 OZ 76 ND ND32/0  OZ 78 82 87 24/29  0/17 0/14 OZ 79 ND ND 4/0 OZ 80 79 75 0/3 ND OZ81 ND ND 28/0  OZ 83 ND ND  7/19 OZ 89 86 81  0/17 OZ 90 81 79 ND OZ 105ND ND 8/0 OZ 107 ND ND 26/4  OZ 108 30 28 28/0  OZ 111 71 68 ND OZ 11988 87 ND OZ 126 ND ND 0/9 OZ 130 ND ND 0/8 OZ 140 ND ND 0/3 OZ 145 80 83ND OZ 148 ND ND 25/0  OZ 151 19 19 ND OZ 152 19 11 ND no dead OZ 153 NDND worm*

[0363] IN VIVO ACTIVITY AGAINST SCHISTOSOMA MANSONI (MICE INFECTED) %reduction of % reduction of schistosomule adult worms growth growth atday at day 49 after per os 21 after per os application of . . . mg/kgapplication of 200 OZ 200 mg/kg TWR (%)/ COMPOUNDS TWR FWR DEAD TESTED(%) (%) WORM (%) 400 600 OZ 154 ND ND 58/0* OZ 156 ND ND 0/6 OZ 157 6568 ND OZ 159 19 19 ND OZ 160  0  0 ND OZ 163 84 80 ND OZ 169  0  0 ND OZ170 ND ND 12/0  OZ 189 ND ND  0/30* OZ 205 84 83  0/12 OZ 207 93 100 32/17 35/21  11/ 24++ OZ 209 ND ND 39/34 16/28+  41/ 21++ OZ 226 ND ND52/0* OZ 256 ND ND 10/19 OZ 271 ND ND 0/6 OZ 277 ND ND 0/0 OZ 279 ND ND 0/12 OZ 281 ND ND 12/15 ARTEMETHER (n2) 81 (n2) 78 (n2) 53/29PRAZIQUANTEL ND ND 93/89 100/100

EXAMPLE 5 Activity of Trioxolanes Against P. berghei

[0364] In the single dose ED₅₀/ED₉₈/ED₉₉ determinations, Moro SPF orNMRI mice (group of three) infected with the ANKA strain of Plasmodiumberghei were treated on day one post-infection. Trioxolanes weredissolved or suspended in the standard suspending vehicle (SSV)* andadministered as single 10, 6, 3, 1, 0.3, and 0.1 mg/kg doses po and sc.The SSV consists of 0.5% w/v CMC, 0.5% v/v benzyl alcohol, 0.4% v/vTween 80, and 0.9% w/v sodium chloride in water. Antimalarial activitywas measured by percent reduction in parasitemia on day threepost-infection. The ED₅₀/ED₉₀ values were calculated by nonlinearfitting. TABLE 5 Compd ED₅₀ (mg/kg) ED₉₀ (mg/kg) ED₉₉ (mg/kg) OZ05 8.712 15 OZ11 4.4 6.2 8.2 OZ27 2.9 5.7 9.9 OZ78 4.2 9.1 17 OZ113 3.6 9.0 19OZ127 2.5 7.6 19 OZ156 1.3 2.6 4.7 OZ175 3.5 6.2 9.9 OZ177 2.1 3.7 5.8OZ179 1.4 3.3 6.6 OZ181 0.63 1.8 4.0 OZ205 1.6 3.3 6.0 OZ207 0.37 1.23.0 OZ209 0.55 1.4 3.0 OZ219 1.6 3.0 5.2 OZ227 2.3 4.0 6.2 OZ235 4.0 7.111 OZ277 0.78 2.0 4.4 OZ279 0.63 1.8 3.9 Artesunate 4.7 19 60 Artelinate4.8 10 18 Artemether 2.2 4.2 7.1 Chloroquine 1.8 3.5 5.9 Mefloquine 4.05.4 6.8

[0365] Table 5 shows ED50/ED90/ED99 data obtained by po administrationof trioxolanes in the SSV formulation. The relatively lipophilicartemether is substantially more active than the more polar artesunateand artelinate. In contrast, the most active trioxolanes (OZ181, OZ207,OZ209)—different salt forms of the same amino trioxolane, and amino andamide trioxolanes OZ277 and OZ279, are relatively polar compounds.

EXAMPLE 6 Dosing of OZ279, OZ277, OZ256, and OZ209

[0366] Based on results of dosing OZ279, OZ277, OZ256, and OZ209 in ratsand dogs, the inventors determined projected optimal dosing of the samecompounds in humans. Artesunate is listed as a reference compound. TABLE6 Parameter Ideal Accept Artes OZ 279 OZ 277 OZ 256 OZ 209 Rat Data IVt1/2 (10 mg/kg) 180 min 60 min 40 100.5 77.2 94.0 150.0 (DHA) OralBioavailability 10 mg/kg >30% >20% not done  37.2 36.9 18.6  12.4 25mg/kg >30% >20% 21  71.1 44.1 51.9  22.4 (DHA) Oral t1/2 (25 mg/kg) 180min 60 min not done 166.8 90.5 73.3 101.5 Dog Data IV t1/2 (10 mg/kg)180 min 60 min not done 177.5 95.0 85.4 182.8 Oral Bioavailability 10mg/kg >30% >20% not done 32.8 (V) 87.9 42.0 (V) 24.5 (V) 25mg/kg >30% >20% not done 55.7 (V) 96.1 38.3 (V) 15.9 (V) Oral t1/2 (10mg/kg) 180 min 60 min not done 195.3 148.1  82.8 127.3 Human DataProjected daily 150 mg 300 mg 150-300 105-154 28-56 91-133 35-70 dose(actual) (30%) (30%) (20%) (20%) mg/day (% BA)

EXAMPLE 7 Effectiveness of Selected OZ Compounds in the Treatment andProphylaxis of Malarial Infections

[0367] In Vitro Antimalarial Assays

[0368] Various OZ compounds were tested by the semiautomatedmicrodilution assay against intraerythrocytic forms of Plasmodiumfalciparum derived from asynchronous stock cultures. The culture mediumused was RPMI 1640 supplemented with 10% human type A⁺ serum, 25 mMHEPES, 25 mM NaHCO₃ (pH 7.3). Human type A⁺ erythrocytes served as hostcells. The culture was kept at 37° C. in an atmosphere of 3% O₂, 4% CO₂,and 93% N₂ in humidified modular chambers.

[0369] Compounds were dissolved in DMSO (10 mg/ml), pre-diluted incomplete culture medium, and titrated in duplicate in serial twofolddilutions over a 64-fold range in 96-well microtiter plates. Afteraddition of the parasite cultures with an initial parasitemia (expressedas the percentage of erythrocytes infected) of 0.75% in a 2.5%erythrocytes suspension, the test plates were incubated under theconditions described above for 72 h. Growth of the parasites cultureswas measured by the incorporation of radiolabelled [³H]-hypoxanthineadded 16 h prior to termination of the test. Fifty percent inhibitoryconcentration (IC₅₀) were estimated by Logit regression analysis.Compounds were tested against reference P. falciparum strains, K1 strain(Thailand resistant to chloroquine) and NF54 strain (an airport strainof unknown origin that is sensitive to standard antimalarials).

[0370] In Vivo Antimalarial Assays

[0371] Moro NMRI male mice (Fu Albino specific pathogen free) weighing18±2 g were infected intravenously (i.v.) with 2×10⁷ P. berghei ANKAstrain-infected erythrocytes from donor mice on day 0 of the experiment.From donor mice with circa 30% parasitemia, heparinized blood was takenand diluted in physiological saline to 10⁸ parasitized erythrocytes perml. An aliquot (0.2 ml) of this suspension was injected i.v. intoexperimental and control groups of mice. In untreated control mice,parasitemia rose regularly to 40 to 50% by day 3 post-infection and 70to 80% by day 4 post-infection. The mice died between days 5 and 7post-infection. Throughout the experiments, mice were kept in groups ofthree or five animals in Makrolon type II cages in an air-conditionedanimal room at 22 to 23° C. A diet with p-aminobenzoic acid (PABA) of 45mg (NAFAG FUTTER© food N° 9009 PAB-45) per kg of body weight, and tapwater is available ad libitum.

[0372] OZ compounds were prepared at an appropriate concentration,either as a solution or a suspension containing SSV (0.5% w/v CMC, 0.5%v/v benzyl alcohol, 0.4% v/v Tween 80, and 0.9% w/v sodium chloride inwater). They were administered per os (p.o.) in a total volume of 0.01ml per gram of mouse. The activity of the compound was determined by avariety of methods outlined in subsequent sections. Survival time wasalso recorded, and survival to day 30 post-infection was considered tobe a cure.

[0373] Determinations of 50, 90, and 99% effective doses (ED₅₀, ED₉₀,and ED₉₉, respectively) were determined after treatment with a singledose only. Mice were treated once on day 1 post-infection (24 h afterinfection). On day 3 post-infection (72 h after infection) blood smearsof all animals were prepared and stained with Giemsa. Parasitemia wasdetermined microscopically, and the difference between the mean value ofthe control group (taken as 100%) and those of the experimental groupswas calculated and expressed as percent reduction. The ED₅₀, ED₉₀, andED₉₉ values were calculated by non-linear fitting with statisticalprogram and were expressed in mg/kg.

[0374] The first experiment conducted consisted of administration of adivided 3×10 mg/kg p.o. dose administered on days 1, 2, and 3post-infection vs. a single 1×30 mg/kg po dose administered on day 1post-infection. On day 4 post-infection, blood smears of all animalswere prepared and stained with Giemsa. Parasitemia was determinedmicroscopically, and the difference between the mean value of thecontrol group (taken as 100%) and those of the experimental groups wascalculated and expressed as percent reduction. Compounds wereadministered orally in the SSV vehicle. The results are shown in Table 7below: TABLE 7 1 × 30 mg/kg 3 × 10 mg/kg Activity Survival ActivitySurvival (%) (days) Cures (%) (days) Cures OZ p.o. SSV p.o. SSV 209100 >30 0/5 100 >30 3\3 271 99.97 14 0/5 100 27.8 4\5 277 99.92 10.4 0/5100 27.6 4\5 279 99.95 14.8 0/5 100 25.4 3\5 301 NA NA NA 100 >30 5\5315 NA NA NA 100 >30 5\5 CQ 99.94 9.5 0/5 99.99 14.3 0/5 MFQ 99.94 20.30/5 99.92 23.3 0/5 AS 83.83 9 0/5 98.62 11 0/5

[0375] As shown by Table 7, a 3×10 mg/kg dose of these trioxolanes curedbetween 3/5 and 5/5 of the infected mice. At this same dose, none of thestandard antimalarial drugs cured any of the infected mice. At the 1×30mg/kg dose, all tested trioxolanes showed activities >99.9% on day 3post-treatment.

[0376] The second experiment consists of administration of divided 3×3mg/kg and 3×1 mg/kg po doses administered on days 1, 2, and 3post-infection. On day 4 post-infection, blood smears of all animalswere prepared and stained with Giemsa. Parasitemia was determinedmicroscopically, and the difference between the mean value of thecontrol group (taken as 100%) and those of the experimental groups wascalculated and expressed as percent reduction. Compounds wereadministered orally in the SSV vehicle. The results are shown in Table8. 3 × 3 mg/kg 3 × 1 mg/kg Activity Survival Activity Survival (%)(days) (%) (days) OZ p.o. SSV Cur s p. . SSV 209 100 16.4 0\5 99.51 9.4271 99.99 16.2 0\5 87 8.8 277 100 14 0\5 83 9.4 279 100 14.8 0\5 83 8.8281 100 12.4 0\5 92 13 288 99 10.2 0\5 49 8.4 289 100 17.2 0\5 41 7.4290 93 10.6 0\5 14 6.8 296 94 9.4 0\5 49 7.8 297 89 9.4 0\5 22 6.4 29899.99 16.4 0\5 93 11 301 100 23 1\5 58 8.8 302 99.51 13.4 0\5 87 13.4305 99.91 12.2 0\5 87 9.6 306 99.75 7.6 0\5 85 11 309 99 9.2 0\5 66 9.4315 99.99 22 0\5 81 12.2 317 100 16.8 0\5 73 11.4 319 99.97 11.2 0\5 9213 320 96 9.6 0\5 50 8.6 323 99.95 14.4 0\5 66 14.4 329 100 27 2\5 99.8611 330 99 12.6 0\5 45 9.2 333 99 10.2 0\5 64 9.4 335 99.99 15.4 0\5 9810 336 100 20.8 0\5 99.14 10.4 337 99.98 14.4 0\5 96 9.4 338 100 25.60\5 98 9.4 339 100 27 3\5 97 9.2 CQ 99.54 10 0\5 25 7.2 MFQ 98 12 0\5 26.2 AM 86 9.4 0\5 51 7.2 AS 78 9.4 0\5 39 6.8

[0377] As shown by Table 8, at the 3×3 mg/kg dose, ten trioxolanes,together with the previously reported OZ209, had activities of 100% andproduced high survival numbers. Of these, OZ301, OZ329, and OZ339 cured1/5, 2/5, and 3/5 of the infected mice, respectively. At the 3×1 mg/kgdose, most of the trioxolanes were more potent than the referenceantimalarial drugs; ten of these had activities >90%. OZ209, OZ329, andOZ336 were the only trioxolanes with activities greater than 99% at the3×1 mg/kg dose.

[0378] Prophylactic activities of the compounds were compared afteradministering po single dose of 100 mg/kg to different groups of fiveanimals at various times before infection. All groups including anuntreated control group, were then infected at the same time.Parasitemia was determined for each animal on day 3 post-infection, andpercent of reduction of the level of parasitemia compared to levels foranimals given no drug is determined. The results are shown in Table 10.TABLE 9 Prophylactic Activity (%) AM AS CQ MFQ 209 256 271 277 279 28172 h - 99.97 99.92 13 99.89 9 14 8 48 h - 57.49 99.92 99.9 29 99.98 7 2745 24 h - 0 6.28 99.92 100 100 82 100 25 97 99.23  0 h 100 92.44 100 100100 100 100 100 100 100

[0379] The unique prophylactic property of OZ209 (3-day protection, sameas MFQ) was found also for OZ27 1.

[0380] It should be appreciated that the Spiro and dispiro1,2,4-trioxolane compositions of this invention may contain trioxolaneswithin the scope of the formulas described above, or prodrugs oranalogues of these compounds or a racemic mixture of either the D or theL form. The invention is also intended to include all biologicallyactive salt forms of the compounds. Also, minor dosage and formulationmodifications of the composition and the ranges expressed herein may bemade and still come within the scope and spirit of the presentinvention.

[0381] Having described the invention with reference to particularcompositions, theories of effectiveness, and the like, it will beapparent to those of skill in the art that it is not intended that theinvention be limited by such illustrative embodiments or mechanisms, andthat modifications can be made without departing from the scope orspirit of the invention, as defined by the appended claims. It isintended that all such obvious modifications and variations be includedwithin the scope of the present invention as defined in the appendedclaims. The claims are meant to cover the claimed components and stepsin any sequence which is effective to meet the objectives thereintended, unless the context specifically indicates to the contrary.

[0382] All articles cited herein and in the following list are herebyexpressly incorporated in their entirety by reference.

CITATIONS de Almeida Barbosa, L.-C. et al., The Design, Synthesis andBiological Evaluation of Some Stable Ozonides With Anti-malarialActivity. J. Chem. Soc. Perkin Trans. I, 1996, 1101-1105.

[0383] de Almeida Barbosa, L.-C. et al., Synthesis of Some StableOozonides With Anti-malarial Activity. J. Chem. Soc. Perkin Trans. I,1992, 3251-3252.

[0384] Cammenga, H. K. et al., Basic principles of thermoanalyticaltechniques and their applications in preparative chemistry. Angew. Chem.Int. Ed. Engl. 1995, 34, 1171-1187.

[0385] Cumming, J. N. et al., Antimalarial activity of artemisinin(qinghaosu) and related trioxanes: mechanism(s) of action. Adv.Pharmacol. 1997. 37, 254-297.

[0386] Dhingra, V. K. et al., Current Status of Artemisinin and ItsDerivatives As Antimalarial Drugs. Life Sci. 2000, 66, 279-300.

[0387] Dong, Y.; Vennerstrom, J. L Peroxidic Antimalarials. Expert Opin.Ther. Patents 2001, 11, 1753-1760.

[0388] Fishwick, J., et al., The Toxicity of Artemisinin and RelatedCompounds on Neuronal and Glial Cells in Culture. Chem.-Biol. Interact.1995, 96, 263-271.

[0389] Griesbaum, K. et al., Diozonides from coozonolyses of suitableO-methyl oximes and ketones. Tetrahedron 1997a, 53, 5463-5470.

[0390] Griesbaum, K. et al., Ozonolyses of O-alkylated ketoximes in thepresence of carbonyl groups: a facile access to ozonides. LiebigsAnn./Recueil. 1997b, 1381-1390.

[0391] Jefford, C. Peroxidic Antimalarials. Adv. Drug Res. 1997, 29,271-325. Kashima, C. et al., Ozonolysis of Five-Membered Heterocycles.J. Het. Chem. 1987, 24, 637-639.

[0392] Meshnick, S. R. et al., Artemisinin and the antimalarialendoperoxides: from herbal remedy to targeted chemotherapy. Microbiol.Rev. 1996, 60, 301-315.

[0393] Park, B. K. et al., Safety Assessment of Peroxide Antimalarials:Clinical and Chemical Perspectives. Br. J. Clin. Pharmacol. 1998, 46,521-529.

[0394] Titulaer, H. A. C., Zuidema, J., and Lugt, C. B. Formulation andpharmacokinetics of artemisinin and its derivatives. Int. J. Pharmaceut.1991, 69, 83-92.

[0395] van Agtmael, M. A. et al., Artemisinin Drugs In the Treatment ofMalaria: From Medicinal Herb to Registered Medication. Trends Pharmacol.Sci. 1999, 20, 199-205.

[0396] Vennerstrom, J. L. et al., Synthesis and Antimalarial Activity ofSixteen Dispiro-1,2,4,5-tetraoxane Analogs of WR 148999: AlkylSubstituted 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes. J. Med. Chem.2000, 43, 2753-2758.

[0397] Vroman, J. A. et al., Current Progress in the Chemistry,Medicinal Chemistry and Drug Design of Artemisinin Based Antimalarials.Curr. Pharm. Design 1999, 5, 101-138.

[0398] Wesche, D. L. et al., Neurotoxicity of artemisinin analogs invitro. Antimicrob. Agents. Chemother. 1994, 38, 1813-1819.

[0399] White, N. J. Clinical pharmacokinetics and pharmacodynamics ofartemisinin and derivatives. Trans. R. Soc. Trop. Med. Hyg. 1994, 88,41-43.

What is claimed is:
 1. A Spiro or dispiro 1,2,4-trioxolane having thefollowing structure:

wherein R₁ and R₂ are the same or different, and are selected from thegroup consisting of hydrogen, substituted or unsubstituted linear orbranched alkyl aryl, and alkaryl groups and substituted or unsubstitutedalicyclic groups that may be interrupted by one or more oxygen, sulfuror nitrogen atoms, substituted or unsubstituted aromatic or heterocyclicgroups that may be interrupted by one or more oxygen, sulfur or nitrogenatoms, a hydroxy group, and a halogen, and further providing that thespirocyclohexyl ring attaching R₁ and R₂ may be interrupted by one ormore oxygen, sulfur, or nitrogen atoms.
 2. The trioxolane of claim 1whereby R₁ is hydrogen and R₂ is (CH₂)_(n)—Y; whereby Y is a functionalgroup selected from the group consisting of an alkyl, ketone, acid,alcohol, amine, amide, sulfonamide, guanidine, ether, ester, oxime,urea, oxime ether, sulfone, lactone, carbamate, semicarbazone, phenyl,and heterocycle; and n is an integer.
 3. The trioxolane of claim 1whereby Y is a non-acidic functional group.
 4. The trioxolane of claim 3whereby Y is a weak base.
 5. The trioxolane of claim 5 whereby Y is anamide.
 6. The trioxolane of claim 2 whereby n=1.
 7. The spiro or dispiro1,2,4-trioxolane of claim 1 wherein the 1,2,4-trioxolane is selectedfrom the group consisting of: OZ271, OZ277, OZ281, OZ279, OZ288, OZ289,OZ290, OZ296, OZ297, OZ298, OZ301, OZ305, OZ309, OZ315, OZ317, OZ319,OZ320, OZ323, OZ329, OZ333, OZ335, OZ336, OZ337, OZ338, and OZ339. 8.The spiro or dispiro 1,2,4-trioxolane of claim 7 wherein the1,2,4-trioxolane is selected from the group consisting of OZ271, OZ277,OZ279, OZ301, OZ305, OZ315, OZ317, OZ319, OZ323, OZ329, OZ338, andOZ339. 9.Cis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methylpropyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate. 10.Cis-adamantane-2-spiro-3′-8′-[(1′-piperazinylcarbonyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate. 11.Cis-Adamantane-2-spiro-3′-8′-[[(1′-piperazinylcarbonyl)amino]methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate. 12.Cis-Adamantane-2-spiro-3′-8′-[[(4′-amino-1′-piperidinyl)carbonyl]methyl]-1′,2′,4′trioxaspiro[4.5]decanep-tosylate.
 13. A pharmaceutical composition for prophylaxis andtreatment of malaria comprising: a malaria prophylaxis or malariatreatment-effective amount of a spiro or dispiro 1,2,4-trioxolane, itsprodrugs and optical isomers thereof, and a pharmaceutically acceptablecarrier, said trioxolane having the following structure:

wherein R₁ and R₂ are the same or different, and are selected from thegroup consisting of hydrogen, substituted or unsubstituted linear orbranched alkyl, aryl, and alkaryl groups and substituted orunsubstituted alicyclic groups that may be interrupted by one or moreoxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromaticor heterocyclic groups that may be interrupted by one or more oxygen,sulfur or nitrogen atoms, a hydroxy group, and a halogen, and furtherproviding that the spirocyclohexyl ring attaching R₁ and R₂ may beinterrupted by one or more oxygen, sulfur, or nitrogen atoms.
 14. Thepharmaceutical composition of claim 13 whereby R₁ is hydrogen and R₂ is(CH₂)_(n)—Y; whereby Y is a functional group selected from the groupconsisting of an alkyl, ketone, acid, alcohol, amine, amide,sulfonamide, guanidine, ether, ester, oxime, urea, oxime ether, sulfone,lactone, carbamate, semicarbazone, phenyl, and heterocycle; and n is aninteger.
 15. The pharmaceutical composition of claim 14 whereby Y is anon-acidic functional group.
 16. The pharmaceutical composition of claim14 whereby Y is a weak base.
 17. The pharmaceutical composition of claim16 whereby Y is an amide.
 18. The pharmaceutical composition of claim 14whereby n=1.
 19. The pharmaceutical composition of claim 13 wherein thetrioxolane is selected from the group consisting of: OZ271, OZ277,OZ281, OZ279, OZ288, OZ289, OZ290, OZ296, OZ297, OZ298, OZ301, OZ305,OZ309, OZ315, OZ317, OZ319, OZ320, OZ323, OZ329, OZ333, OZ335, OZ336,OZ337, OZ338, and OZ339.
 20. The pharmaceutical composition of claim 19wherein the trioxolane is selected from the group consisting of OZ271,OZ277, OZ279, OZ301, OZ305, OZ315, OZ317, OZ319, OZ323, OZ329, OZ338,and OZ339.
 21. The pharmaceutical composition of claim 13 wherein the1,2,4-trioxolane iscis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methylpropyl)amino]carbonylmethyl]-1′,2′,4′-trioxaspiro[4.5]decane p-tosylate.
 22. Thepharmaceutical composition of claim 13 wherein the 1,2,4-trioxolane iscis-adamantane-2-spiro-3′-8′-[(1′-piperazinylcarbonyl)methyl]-1′,2′,4′-trioxaspiro[4.5]decanep-tosylate.
 23. The pharmaceutical composition of claim 13 that issuitable for administration by a method selected from the groupconsisting of oral, subcutaneous, intravenous, intranasal, rectal,sublingual, and buccal.
 24. A method of preventing or treating malariacomprising: administrating a malaria prevention or malaria treatmenteffective amount of a spiro or dispiro 1,2,4-trioxolane in apharmaceutically acceptable carrier, said trioxolane having thefollowing structure:

wherein R₁ and R₂ are the same or different, and are selected from thegroup consisting of hydrogen, substituted or unsubstituted linear orbranched alkyl, aryl, and alkaryl groups and substituted orunsubstituted alicyclic groups that may be interrupted by one or moreoxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromaticor heterocyclic groups that may be interrupted by one or more oxygen,sulfur or nitrogen atoms, a hydroxy group, and a halogen, and furtherproviding that the spirocyclohexyl ring attaching R₁ and R₂ may beinterrupted by one or more oxygen, sulfur, or nitrogen atoms.
 25. Themethod of claim 24 whereby R₁ is hydrogen and R₂ is (CH₂)_(n)—Y; wherebyY is a functional group selected from the group consisting of an alkyl,ketone, acid, alcohol, amine, amide, sulfonamide, guanidine, ether,ester, oxime, urea, oxime ether, sulfone, lactone, carbamate,semicarbazone, phenyl, and heterocycle; and n is an integer.
 26. Themethod of claim 24 wherein the trioxolane is administered in a dose ofbetween about 0.1-1000 mg/kg/day.
 27. The method of claim 26 wherein thetrioxolane is administered in a dose of between about 1-100 mg/kg/day.28. The method of claim 24 wherein the trioxolane is administered in asingle dose.
 29. The method of claim 24 wherein the trioxolane isadministered in divided doses.
 30. The method of claim 24 wherein thetrioxolane is administered in a malaria-preventive dose beginning 1-2weeks prior to malaria exposure and ending 1-2 weeks post exposure. 31.A method of claim 24 wherein the trioxolane is administered in amalaria-curative dose over 1-10 days.
 32. A method of manufacturing acomposition for prophylaxis and treatment of malaria comprising: mixinga malaria prophylaxis or malaria treatment-effective amount of a spiroor dispiro 1,2,4-trioxolane, its prodrugs and optical isomers thereof,with a pharmaceutically acceptable carrier, said trioxolane having thefollowing structure:

wherein R₁ and R₂ are the same or different, and are selected from thegroup consisting of hydrogen, substituted or unsubstituted linear orbranched alkyl, aryl, and alkaryl groups and substituted orunsubstituted alicyclic groups that may be interrupted by one or moreoxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromaticor heterocyclic groups that may be interrupted by one or more oxygen,sulfur or nitrogen atoms, a hydroxy group, and a halogen, and furtherproviding that the spirocyclohexyl ring attaching R₁ and R₂ may beinterrupted by one or more oxygen, sulfur, or nitrogen atoms.
 33. Amethod of treating cancer comprising: administrating a cancer treatmenteffective amount of a spiro or dispiro 1,2,4-trioxolane in apharmaceutically acceptable carrier, said trioxolane having thefollowing structure:

wherein R₁ and R₂ are the same or different, and are selected from thegroup consisting of hydrogen, substituted or unsubstituted linear orbranched alkyl, aryl, and alkaryl groups and substituted orunsubstituted alicyclic groups that may be interrupted by one or moreoxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromaticor heterocyclic groups that may be interrupted by one or more oxygen,sulfur or nitrogen atoms, a hydroxy group, and a halogen, and furtherproviding that the spirocyclohexyl ring attaching R₁ and R₂ may beinterrupted by one or more oxygen, sulfur, or nitrogen atoms.
 34. Amethod of prophylaxis or treatment of schistosomiasis comprising:administrating a schistosomiasis prophylaxis or treatment effectiveamount of a spiro or dispiro 1,2,4-trioxolane in a pharmaceuticallyacceptable carrier, said trioxolane having the following structure:

wherein R₁ and R₂ are the same or different, and are selected from thegroup consisting of hydrogen, substituted or unsubstituted linear orbranched alkyl, aryl, and alkaryl groups and substituted orunsubstituted alicyclic groups that may be interrupted by one or moreoxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromaticor heterocyclic groups that may be interrupted by one or more oxygen,sulfur or nitrogen atoms, a hydroxy group, and a halogen, and furtherproviding that the spirocyclohexyl ring attaching R₁ and R₂ may beinterrupted by one or more oxygen, sulfur, or nitrogen atoms.
 35. Amethod of synthesizing a dispiro 1,2,4-trioxolane comprising: treating atrioxolane having a functional group selected from the group consistingof a ketone, an aldehyde, an ester, and a phthalimide with a reagent toform a compound selected from the group consisting of lactone, alcohol,oxime ether, hydrazone, ketal, acetal, amine, and acid.
 36. The methodof claim 35 wherein the trioxolane has a ketone or an aldehydefunctional group, and is treated with an oxidizing agent to form alactone or an acid.
 37. The method of claim 36 wherein the trioxolanehas a ketone or an aldehyde functional group, and is treated with areducing agent to form an amine or an alcohol.
 38. The method of claim36 wherein the trioxolane has a ketone or an aldehyde functional group,and is treated with a hydroxylamine or a hydrazine to form an oximeether or a hydrazone, respectively.
 39. The method of claim 35 whereinthe trioxolane has a ketone or an aldehyde functional group, and istreated with one or more diols and/or alcohols to form a ketal oracetal.
 40. The method of claim 36 whereby the trioxolane is OZ05. 41.The method of claim 40 whereby OZ05 is treated with a heteroaryllithium,aryllithium, or alkyllithium reagent to form the corresponding tertiaryalcohol.
 42. The method of claim 37 wherein the trioxolane has an esterfunctional group, and is treated with a reducing agent to form analcohol.
 43. The method of claim 42 whereby the trioxolane is selectedfrom the group consisting of OZ70 and OZ61.
 44. The method of claim 43whereby OZ70 is treated with a reducing agent to form OZ119.
 45. Themethod of claim 43 whereby OZ61 is treated with a reducing agent to formOZ89.
 46. The method of claim 39 wherein the trioxolane has an esterfunctional group, and is treated with a hydrolyzing agent to form anacid.
 47. The method of claim 46 wherein the hydrolyzing agent isaqueous potassium hydroxide.
 48. The method of claim 46 wherein OZ61 istreated with a hydrolyzing agent to form OZ78.
 49. The method of claim35 wherein the trioxolane has an phthalimide functional group, and istreated with a deprotecting reagent to form an amine.
 50. The method ofclaim 49 whereby the phthalimide is selected from the group consistingof OZ136, OZ146, and OZ167.
 51. The method of claim 50 whereby OZ136 istreated with a deprotecting reagent to form OZ137.
 52. The method ofclaim 50 whereby OZ146 is treated with a deprotecting reagent to formOZ181.
 53. The method of claim 52 whereby OZ167 is treated with adeprotecting reagent to form OZ269.
 54. The method of claim 53 whereinthe deprotecting reagent is hydrazine.
 55. A spiro or dispiro1,2,4-trioxolane having the following structure:

whereby R₃ is (CH₂)_(n)—Y, and further providing that Y is a weak baseamide; and n is an integer.
 56. The trioxolane of claim 55 whereby n=1.